Dimeric p-selectin inhibitors and uses thereof

Abstract

Provided herein are dimeric P-selecting inhibitors ("conjugates") comprising two P- selecting binding glycopeptides conjugated via a linker. In certain embodiments, the conjugates described herein have increased affinity for P-selectin relative to existing inhibitors.

Description

[0001] DIMERIC P-SELECTIN INHIBITORS AND USES THEREOF RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent application, 63 / 704,498, filed October 7, 2024, the entire contents of which is incorporated herein by reference. GOVERNMENT SUPPORT

[0002] This invention was made with government support under HL128237, GM116196, and DK107405, awarded by the National Institutes of Health. The government has certain rights in the invention. BACKGROUND

[0003] The selectin family of cell adhesion molecules, together with their glycoconjugate ligands, participate in leukocyte trafficking to sites of inflammation and to lymphoid organs. P- and E- selectins are expressed on activated vascular endothelial cells where they mediate initial tethering and rolling of leukocytes on endothelial cells by binding to P-selectin glycopeptide ligand-1 (PSGL-1) present on the surface of leukocytes. P-selectin is also expressed on activated platelets. L-selectin is expressed on the surface of leukocytes and mediates leukocyte-leukocyte interactions by binding to PSGL-1 present on the surface of other leukocytes promoting leukocyte accumulation to the inflammatory sites. Selectins recognize the sialyl Lewis x epitope (sLex or sLexNeuAca2-3Galpi-4(Fucal-3)GlcNAcpi-) on glycoconjugate ligands. However, selectin binding to sLex determinant alone is low affinity and is necessary but not sufficient for physiological interactions. Thus, selectins require additional post-translational modifications or peptide components for high-affinity binding to their ligands. P- and L-selectin both bind to the extreme N-terminus of PSGL-1 and interact with three clustered tyrosine sulfate residues and a nearby core-2-based O-glycan with sialyl Lewis x epitope (C2-SLex). The N-terminus of human PSGL-1 contains three potential tyrosine sulfation sites (Y46, Y48 and Y51) and two potential O-glycan attachment sites (T44 and T57).

[0004] Several small molecule inhibitors and protein therapeutics aimed at blocking PSGL-l / P- selectin interactions are already in clinical trials. Certain candidates pose production, stability, and immunity issues. Thus, there is a need for molecules that bind to selectins with high specificity and affinity, which in turn inhibit selectin mediated cell-cell interactions that have desirable pharmacological properties.

[0002] 1 / 89#14461419v1 SUMMARY OF THEINVENTION

[0005] Provided herein are dimeric P-selecting inhibitors (“conjugates”) comprising two P- selecting binding glycopeptides conjugated via a linker. In certain embodiments, the conjugates described herein have increased affinity for P-selectin relative to existing inhibitors.

[0006] In one aspect, provided herein are conjugates and pharmaceutically acceptable salts thereof comprising Formula (I): (I), wherein each of P1and P2are independently glycopeptides comprising the amino acid sequence: Y1X1Y2X2X3Y3X4X5X6Z1X7W1(SEQ ID NO: 1), wherein: W1is threonine or serine conjugated with a saccharide or polysaccharide; X1, X2, X3, X4, X5, X6, and X7are each independently any amino acid; Y1, Y2, and Y3are each independently tyrosine, phenylalanine, or phenylglycine, and wherein Y1, Y2, and Y3are each independently unsubstituted or substituted with -SO3H, -CH2SO3H, -CF2SO3H, -CO2H, -CONH2, -NHSO2CH3, -SO2NH2, or -CH2PO3H; optionally wherein at least one of Y1, Y2, and Y3is substituted with -CH2SO3H; Z1is proline or hydroxyproline; and L1is a linker.

[0007] In another aspect, provided herein are pharmaceutical compositions comprising a conjugate of the present disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0008] In one aspect, provided herein are methods comprising administering to a subject a conjugate, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition described herein.

[0009] In another aspect, provided are methods of inhibiting P-selectin binding to PSGL-1, comprising contacting P-selectin with a conjugate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, described herein.

[0010] In one aspect, provided herein are methods of treating or preventing cardiovascular disease, atherosclerosis, atherosclerotic lesions, thrombus formation, thromboembolism, stroke, sickle cell disease, proliferative disease, metabolic syndrome, ischemia reperfusion injury, or myocardial infarction in a subject in need thereof, comprising administering to the subject an effective amount of a conjugate, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition of described herein.

[0011] In another aspect, provided are methods of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a conjugate, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition of

[0003] 2 / 89#14461419v1 the present disclosure.

[0012] In one aspect, provided are methods of thromboprophylaxis, comprising administering to a subject diagnosed with cancer an effective amount of a conjugate, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition described herein.

[0013] In another aspect, provided herein are methods of treating or preventing allergy or lung disease in a subject in need thereof, comprising administering to the subject an effective amount of a conjugate, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition of the present disclosure.

[0014] In one aspect, provided herein are conjugates, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions described herein, for use in any method defined herein. In another aspect, provided are uses of a conjugate described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, in the preparation of a medicament.

[0015] The details of certain embodiments of the disclosure are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the disclosure will be apparent from the Definitions, Examples, Figures, and Claims. It should be understood that the aspects described herein are not limited to specific embodiments, methods, or configurations, and as such can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting. BRIEFDESCRIPTION OF THEDRAWINGS

[0016] The accompanying drawings, which constitute a part of this specification, illustrate several embodiments of the disclosure and together with the description, provide non-limiting examples of the disclosure.

[0017] FIGs.1A-1F show P-selectin-Fc chimera binding to primary mouse monocytes and neutrophils by flow cytometry. FIG.1A shows inhibition data for CG4_KL1 (n = 4). FIG.1B shows inhibition data for CG4_KL2 (n = 4). FIG.1C shows inhibition data for CG4_KL3 (n = 4). FIG.1D shows inhibition data for G4_KL1 (n = 4). FIG.1E shows inhibition data for G4_KL2 (n = 4). FIG.1F shows inhibition data for G4_KL3 (n = 4).

[0018] FIGs.2A-2D show P-selectin-Fc chimera binding to primary human monocytes and neutrophils. FIG.2A shows inhibition data for CG4_KL1 (n = 4). FIG.2B shows inhibition data for CG4_KL2 (n = 4). FIG.2C shows inhibition data for P-G4 (n = 5). FIG.2D shows inhibition data for G4 (n = 5).

[0019] FIGs.3A-3B show inhibition of murine platelet-leukocyte aggregation. FIG.3A (left)

[0004] 3 / 89#14461419v1 shows dose dependent inhibition of platelet-neutrophil aggregation by CG4_KL1 (n = 3-5). FIG.3A (right) shows dose dependent inhibition of platelet-monocyte aggregation by CG4_KL1 (n = 3-5). FIG.3B (left) shows dose dependent inhibition of platelet-neutrophil aggregation by CG4_KL2 (n = 3-5). FIG.3B (right) shows dose dependent inhibition of platelet-monocyte aggregation by CG4_KL2 (n = 3-5).

[0020] FIGs.4A-4B show inhibition of human platelet-leukocyte aggregation. FIG.4A (left) shows dose dependent inhibition of platelet-neutrophil aggregation by CG4_KL1 (n = 4-6). FIG.4A (right) shows dose dependent inhibition of platelet-monocyte aggregation by CG4_KL1 (n = 4-6). FIG.4B (left) shows dose dependent inhibition of platelet-neutrophil aggregation by CG4_KL2 (n = 4-6). FIG.4B (right) shows dose dependent inhibition of platelet-monocyte aggregation by CG4_KL2 (n = 4-6).

[0021] FIGs.5A-5D show chemical sequences and structures. FIG.5A shows N-terminal monomer and dimer sequences. FIG.5B shows C-terminal monomer and dimer sequences. FIG.5C shows the linker structure of KL1, KL2, and KL3. FIG.5D shows the tetrameric glycan structure.

[0022] FIG.6 shows dose-response curves of the non-pegylated dimer CG4_KL2 (left) and PEGylated-CG4_KL2 (P-dimer) (right). Compounds (0-30 μM) were incubated with mouse neutrophils and monocytes. Flow cytometry was used to evaluate the percent binding inhibition of species appropriate P-selectin chimera to neutrophils or monocytes produced by the various dimers as compared to phosphate buffered saline control. Both dimers inhibit P-selectin leukocyte interactions in a dose-dependent manner. Data are represented as mean ± SEM, n = 3.

[0023] FIG.7 shows the results of in vivo treatment efficacy in C57BL / 6 mice. P-dimer (0.4 µmol / kg) or saline vehicle were administered by daily subcutaneous (SC) dosing with vena cava injury occurring 4 hours after the fourth dose and thrombus harvested 24 hours after the fifth and final dose. The vena cava and associated thrombus, immediately below the renal veins to just above the bifurcation, was excised 48 hours after injury for determination of wet thrombus weight. P-dimer significantly inhibited venous thrombosis (***p = 0.0003).

[0024] FIG.8 shows the synthesis product of an IPBA bearing propargylated dimeric peptide.

[0025] FIG.9 shows the synthesis product of the IPBA bearing dimeric glycosulfopeptide. FIG.10 shows dose-response curves of t IPBA-CG4_KL2 glycopeptide dimer (IPBA-dimer). The compound (0-30 μM) was incubated with mouse neutrophils and monocytes. Flow cytometry was used to evaluate the percent binding inhibition of species appropriate P-selectin chimera to neutrophils or monocytes produced by IPBA-dimer as compared to phosphate buffered saline control. IPBA-dimer inhibits P-selectin leukocyte interactions in a dose- dependent manner. Data are represented as mean ± SEM, n = 3.

[0005] 4 / 89#14461419v1 DEFINITIONS

[0026] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Michael B. Smith, March’s Advanced Organic Chemistry, 7thEdition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0027] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0028] Unless otherwise provided, formulae and structures depicted herein include peptides that do not include isotopically enriched atoms, and also include peptides that include isotopically enriched atoms (“isotopically labeled derivatives”). For example, peptides having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of19F with18F, or the replacement of a carbon by a13C- or14C-enriched carbon are within the scope of the disclosure. Such peptides are useful, for example, as analytical tools or probes in biological assays. The term “isotopes” refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons.

[0006] 5 / 89#14461419v1

[0029] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “C1-6alkyl” encompasses, C1, C2, C3, C4, C5, C6, C1–6, C1–5, C1–4, C1–3, C1–2, C2–6, C2–5, C2–4, C2–3, C3–6, C3–5, C3–4, C4–6, C4–5, and C5–6 alkyl.

[0030] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.

[0031] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0032] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1–20alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1–6alkyl”). Examples of C1–6alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tert- amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), n-dodecyl (C12), and the like.

[0033] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“C1–20haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include –CHF2, −CH2F, −CF3, −CH2CF3, −CF2CF3, −CF2CF2CF3, −CCl3, −CFCl2, −CF2Cl, and the like.

[0034] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1–20alkyl”).

[0035] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or

[0007] 6 / 89#14461419v1 4 double bonds). In some embodiments, an alkenyl group has 1 to 20 carbon atoms (“C1-20 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3or ) may be in the (E)- or (Z)- configuration.

[0036] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 1 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20alkenyl”).

[0037] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 1 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C1-20alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl).

[0038] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and / or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 1 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC1–20alkynyl”).

[0039] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the

[0008] 7 / 89#14461419v1 carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.

[0040] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 7-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.

[0041] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system.

[0042] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In certain embodiments, the heteroaryl is substituted or

[0009] 8 / 89#14461419v1 unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl / heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom or the ring that does not contain a heteroatom.

[0043] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I).

[0044] The term “acyl” refers to a group having the general formula −C(=O)Raa, −C(=O)ORaa, −C(=S)S(Raa), −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)SRaa, and −C(=NRbb)N(Rbb)2, wherein Raaand Rbbare as defined herein. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.

[0045] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.

[0046] A chemical moiety is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl,

[0010] 9 / 89#14461419v1 heteroaryl, acyl groups are optionally substituted. In general, the term “substituted” when referring to a chemical group means that at least one hydrogen present on the group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The present disclosure is not limited in any manner by the exemplary substituents described herein.

[0047] Exemplary substituents include, but are not limited to, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−, −N(ORcc)Rbb, −SH, −SRaa, −SCN, −SSRcc, −C(=O)Raa, −CO2H, −CHO, −C(ORcc)2, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −OC(=NRbb)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −C(=O)NRbbSO2Raa, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa, −S(=O)Raa, −OS(=O)Raa, −Si(Raa)3, −OSi(Raa)3 −SC(=O)ORaa, −SC(=O)Raa, −P(=O)(Raa)2, −P(=O)(ORcc)2, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, −P(=O)(N(Rbb)2)2, −OP(=O)(N(Rbb)2)2, −NRbbP(=O)(Raa)2, −NRbbP(=O)(ORcc)2, −NRbbP(=O)(N(Rbb)2)2, −P(Rcc)2, −P(ORcc)2, −P(Rcc)3+X−, −P(ORcc)3+X−, −P(Rcc)4, −P(ORcc)4, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1–20alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl; wherein X−is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; wherein: each instance of Raais, independently, selected from C1–20 alkyl, C1–20 perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2,

[0011] 10 / 89#14461419v1 −C(=O)SRcc, −C(=S)SRcc, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1–20 alkyl, C1–20perhaloalkyl, C1–20alkenyl, C1–20alkynyl, heteroC1–20alkyl, heteroC1–20alkenyl, heteroC1–20alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; each instance of Rccis, independently, selected from hydrogen, C1–20alkyl, C1–20perhaloalkyl, C1–20 alkenyl, C1–20 alkynyl, heteroC1–20 alkyl, heteroC1–20 alkenyl, heteroC1–20 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; and each X−is a counterion.

[0048] In certain embodiments, each substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2.

[0049] The terms “polysaccharide” and “oligosaccharide” are used interchangeably herein.

[0050] The terms “peptide” and “polypeptide” are used interchangeably and refer to a polymer of amino acid residues linked together by peptide bonds. The terms also include proteins, and refer to peptides, polypeptides, and proteins, of any size, structure, or function. Typically, a peptide will be at least three amino acids long, or at least the length required by an amino acid sequence provided herein. Peptides provided herein can include natural amino acids and / or unnatural amino acids (i.e., compounds that do not occur in nature but that can be incorporated into a peptide chain) in any combination. One or more of the amino acids in a peptide may be modified, for example, by the addition of a chemical entity such as a carbohydrate group, a hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl group, a fatty acid group, a linker for conjugation or functionalization, or other modification. A peptide may be a fragment or modified version of a naturally occurring peptide or protein. A peptide may be naturally occurring, recombinant, synthetic, or any combination of these.

[0051] Peptides also include peptoids. “Peptoids” are peptides comprising one or more N- substituted glycine residues.

[0052] The term “amino acid” refers to a molecule containing both an amino group and a carboxyl group. Amino acids include alpha-amino acids (the generic structure of which is depicted below) as well as beta-amino acids. Each amino acid referred to herein may be denoted by a 1- to 4-letter code.

[0012] 11 / 89#14461419v1R' ROH H2N α O alpha–amino acid

[0053] Suitable amino acids include, without limitation, natural alpha–amino acids such as D– and L–isomers of the 20 common naturally occurring alpha–amino acids found in peptides (e.g., A, R, N, C, D, Q, E, G, H, I, L, K, M, F, P, S, T, W, Y, V, as provided below), and unnatural alpha–amino acids.

[0054] Exemplary natural alpha-amino acids (with one-letter code provided in parentheses) include L–alanine (A), L–arginine (R), L–asparagine (N), L–aspartic acid (D), L–cysteine (C), L–glutamic acid (E), L–glutamine (Q), glycine (G), L–histidine (H), L–isoleucine (I), L–leucine (L), L–lysine (K), L–methionine (M), L–phenylalanine (F), L–proline (P), L–serine (S), L– threonine (T), L–tryptophan (W), L–tyrosine (Y), and L–valine (V).

[0055] Exemplary unnatural alpha-amino acids include D–arginine, D–asparagine, D–aspartic acid, D–cysteine, D–glutamic acid, D–glutamine, D–histidine, D–isoleucine, D–leucine, D– lysine, D–methionine, D–phenylalanine, D–proline, D–serine, D–threonine, D–tryptophan, D– tyrosine, D–valine, Di-vinyl, α-methyl-alanine (Aib), α-methyl-arginine, α-methyl-asparagine, α-methyl-aspartic acid, α-methyl-cysteine, α-methyl-glutamic acid, α-methyl-glutamine, α- methyl-histidine, α-methyl-isoleucine, α-methyl-leucine, α-methyl-lysine, α-methyl- methionine, α-methyl-phenylalanine, α-methyl-proline, α-methyl-serine, α-methyl-threonine, α-methyl-tryptophan, α-methyl-tyrosine, α-methyl-valine, norleucine, and terminally unsaturated alpha–amino acids. There are many known unnatural amino acids any of which may be included in the peptides of the present disclosure. See for example, S. Hunt, The Non–Protein Amino Acids: In Chemistry and Biochemistry of the Amino Acids, edited by G. C. Barrett, Chapman and Hall, 1985. Unnatural amino acids also include amino acids comprising nitrogen substituents (e.g., N-substituted glycines).

[0056] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO3−, HSO4–, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p– toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like),

[0013] 12 / 89#14461419v1 carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5-(CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO43−, B4O72−, SO42−, S2O32−, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0057] The following definitions are more general terms used throughout the present application.

[0058] As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of this invention include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0059] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well

[0014] 13 / 89#14461419v1 known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4 alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0060] The terms “composition” and “formulation” are used interchangeably.

[0061] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease.

[0015] 14 / 89#14461419v1

[0062] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.

[0063] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0064] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0065] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses.

[0066] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibition of PSGL-1 / P-selectin binding. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a disease or condition recited herein (e.g., VTE).

[0016] 15 / 89#14461419v1

[0067] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibition of PSGL-1 / P-selectin binding. In certain embodiments, a prophylactically effective amount is an amount sufficient for treating a disease or condition recited herein (e.g., VTE).

[0068] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population.

[0069] As used herein the term “inhibit” or “inhibition” in the context of proteins, for example, in the context of P-selectin, refers to prevention of binding or reduction of ligand binding to the receptor. In some embodiments, the term refers to a reduction of the level of protein activity, e.g., P-selectin-mediated activity, or downstream effects, to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline level of activity. In some embodiments, the term refers to a reduction of the level of activity, e.g., P-selectin- mediated activity, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of activity. Diseases and Disorders

[0070] The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. See e.g., Stedman’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990. Exemplary cancers include, but are not limited to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer; benign monoclonal gammopathy; biliary cancer (e.g., cholangiocarcinoma); bladder cancer;

[0017] 16 / 89#14461419v1 breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; ocular cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., stomach adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer)); hematopoietic cancers (e.g., leukemia such as acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma), follicular lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma (CLL / SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma / leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia / lymphoma as described above; and multiple myeloma (MM)), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain disease); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer

[0018] 17 / 89#14461419v1 (e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrome (HES)); neuroblastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor); osteosarcoma (e.g.,bone cancer); ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary adenocarcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors); penile cancer (e.g., Paget’s disease of the penis and scrotum); pinealoma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).

[0071] The term “cardiovascular disease” refers to diseases and disorders of the heart and circulatory system. Exemplary cardiovascular diseases, including cholesterol- or lipid-related disorders, include, but are not limited to acute coronary syndrome, angina, arrhythmia, arteriosclerosis, atherosclerosis, carotid atherosclerosis, cerebrovascular disease, cerebral infarction, congestive heart failure, congenital heart disease, coronary heart disease, coronary artery disease, coronary plaque stabilization, dyslipidemias, dyslipoproteinemias, endothelium dysfunctions, familial hypercholeasterolemia, familial combined hyperlipidemia, hypoalphalipoproteinemia, hypertriglyceridemia, hyperbetalipoproteinemia, hypercholesterolemia, hypertension, hyperlipidemia, intermittent claudication, ischemia, ischemia reperfusion injury, ischemic heart diseases, cardiac ischemia, metabolic syndrome, multi-infarct dementia, myocardial infarction, obesity, peripheral vascular disease, reperfusion injury, restenosis, renal artery atherosclerosis, rheumatic heart disease, stroke, thrombotic

[0019] 18 / 89#14461419v1 disorder, transitory ischemic attacks, and lipoprotein abnormalities associated with Alzheimer's disease, obesity, diabetes mellitus, syndrome X, impotence, multiple sclerosis, Parkinson's diseases inflammatory diseases, lesions, thrombus formation, and thromboembolism.

[0072] “Metabolic disorder” or “metabolic syndrome” refers to any disorder or group of disorders that involves an alteration in the normal metabolism of carbohydrates, lipids, proteins, nucleic acids, or a combination thereof. A metabolic disorder is associated with either a deficiency or excess in a metabolic pathway resulting in an imbalance in metabolism of nucleic acids, proteins, lipids, and / or carbohydrates. Certain of these diseases may be associated with or increase the risk of developing diabetes, heart disease, stroke, or all three. Factors affecting metabolism include, and are not limited to, the endocrine (hormonal) control system (e.g., the insulin pathway, the enteroendocrine hormones including GLP-1, PYY or the like), the neural control system (e.g., GLP-1 in the brain), or the like. Examples of metabolic disorders and syndromes include, but are not limited to, diabetes (e.g., Type I diabetes, Type II diabetes, gestational diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and obesity.

[0073] The term “lung disease” or “pulmonary disease” refers to a disease of the lung. Examples of lung diseases include, but are not limited to, bronchiectasis, bronchitis, bronchopulmonary dysplasia, interstitial lung disease, occupational lung disease, emphysema, cystic fibrosis, acute respiratory distress syndrome (ARDS), severe acute respiratory syndrome (SARS), asthma (e.g., intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma), chronic bronchitis, chronic obstructive pulmonary disease (COPD), emphysema, interstitial lung disease, sarcoidosis, asbestosis, aspergilloma, aspergillosis, pneumonia (e.g., lobar pneumonia, multilobar pneumonia, bronchial pneumonia, interstitial pneumonia), pulmonary fibrosis, pulmonary tuberculosis, rheumatoid lung disease, pulmonary embolism, and lung cancer (e.g., non-small-cell lung carcinoma (e.g., adenocarcinoma, squamous-cell lung carcinoma, large-cell lung carcinoma), small-cell lung carcinoma). DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0074] There is a need to develop P-selectin inhibitors that exhibit both high affinity and specificity. Provided herein are dimeric P-selecting inhibitors (“conjugates”) comprising two P- selecting binding glycopeptides conjugated via a linker. In certain embodiments, the conjugates described herein have increased affinity for P-selectin relative to existing inhibitors.

[0075] In one aspect, provided herein are conjugates and pharmaceutically acceptable salts thereof comprising Formula (I): (I),

[0020] 19 / 89#14461419v1 wherein each of P1and P2are independently glycopeptides comprising the amino acid sequence: Y1X1Y2X2X3Y3X4X5X6Z1X7W1(SEQ ID NO: 1), wherein: W1is threonine or serine conjugated with a saccharide or polysaccharide; X1, X2, X3, X4, X5, X6, and X7are each independently any amino acid; Y1, Y2, and Y3are each independently tyrosine, phenylalanine, or phenylglycine, and wherein Y1, Y2, and Y3are each independently unsubstituted or substituted with -SO3H, - CH2SO3H, -CF2SO3H, -CO2H, -CONH2, -NHSO2CH3, -SO2NH2, or -CH2PO3H; optionally wherein at least one of Y1, Y2, and Y3is substituted with -CH2SO3H; Z1is proline or hydroxyproline; and L1is a linker.

[0076] In some embodiments, each of P1and P2are conjugated to L1via their N-termini. In certain embodiments, each of P1and P2are conjugated to L1via their C-termini. In some embodiments, P1is conjugated to L1via its N-terminus, and P2is conjugated to L1via its C- terminus. In certain embodiments, P1is conjugated to L1via its C-terminus, and P2is conjugated to L1via its N-terminus.

[0077] In some embodiments, P1and P2comprise the same amino acid sequence. In certain embodiments, P1and P2comprise different amino acid sequences. In some embodiments, P1and P2are the same glycopeptide. In some embodiments, P1and P2are different glycopeptides.

[0078] In some embodiments, P1and P2independently comprise one of the following amino acid sequences: Y1EY2LDY3DFLZ1EW1(SEQ ID NO: 2), Y1EY2LDY3DFLZ1EW1EP (SEQ ID NO: 3), Y1EY2LDY3DFLZ1EW1EPL (SEQ ID NO: 4), EY1EY2LDY3DFLZ1EW1(SEQ ID NO: 5), EY1EY2LDY3DFLZ1EW1E (SEQ ID NO: 6), EY1EY2LDY3DFLZ1EW1EP (SEQ ID NO: 7), EY1EY2LDY3DFLZ1EW1EPL (SEQ ID NO: 8), KEY1EY2LDY3DFLZ1EW1(SEQ ID NO: 9), KEY1EY2LDY3DFLZ1EW1E (SEQ ID NO: 10), KEY1EY2LDY3DFLZ1EW1EP (SEQ ID NO: 11), KEY1EY2LDY3DFLZ1EW1EPL (SEQ ID NO: 12), EY1EY2LDY3DFLZ1EW1K (SEQ ID NO: 13), EY1EY2LDY3DFLZ1EW1EK (SEQ ID NO: 14), EY1EY2LDY3DFLZ1EW1EPK (SEQ ID NO: 15), or EY1EY2LDY3DFLZ1EW1EPLK (SEQ ID NO: 16).

[0021] 20 / 89#14461419v1

[0079] In certain embodiments, at least one of Y1, Y2, and Y3is phenylalanine substituted with - SO3H, -CH2SO3H, -CF2SO3H, -CO2H, -CONH2, -NHSO2CH3, -SO2NH2, or -CH2PO3H. In certain embodiments, at least two of Y1, Y2, and Y3are phenylalanine substituted with -SO3H, - CH2SO3H, -CF2SO3H, -CO2H, -CONH2, -NHSO2CH3, -SO2NH2, or -CH2PO3H. In certain embodiments, Y1, Y2, and Y3are phenylalanine substituted with -SO3H, -CH2SO3H, -CF2SO3H, -CO2H, -CONH2, -NHSO2CH3, -SO2NH2, or -CH2PO3H.

[0080] In certain embodiments, at least one of Y1, Y2, and Y3is substituted with -CH2SO3H. In certain embodiments, at least two of Y1, Y2, and Y3are substituted with -CH2SO3H. In some embodiments, each of Y1, Y2, and Y3are substituted with -CH2SO3H. In certain embodiments, Y1, Y2, and Y3are each phenylalanine. In some embodiments, at least one of Y1, Y2, and Y3is phenylalanine substituted with -CH2SO3H. In some embodiments, at least two of Y1, Y2, and Y3is phenylalanine substituted with -CH2SO3H. In some embodiments, Y1, Y2, and Y3are each phenylalanine substituted with -CH2SO3H.

[0081] In certain embodiments, at least one of Y1, Y2, and Y3is tyrosine substituted with -SO3H, -CH2SO3H, -CF2SO3H, -CO2H, -CONH2, -NHSO2CH3, -SO2NH2, or -CH2PO3H. In certain embodiments, at least two of Y1, Y2, and Y3are tyrosine substituted with -SO3H, -CH2SO3H, -CF2SO3H, -CO2H, -CONH2, -NHSO2CH3, -SO2NH2, or -CH2PO3H. In certain embodiments, Y1, Y2, and Y3are tyrosine substituted with -SO3H, -CH2SO3H, -CF2SO3H, -CO2H, -CONH2, -NHSO2CH3, -SO2NH2, or -CH2PO3H.

[0082] In certain embodiments, at least one of Y1, Y2, and Y3is substituted with -SO3H. In certain embodiments, at least two of Y1, Y2, and Y3are substituted with -SO3H. In some embodiments, each of Y1, Y2, and Y3are substituted with -SO3H. In certain embodiments, Y1, Y2, and Y3are each tyrosine. In some embodiments, at least one of Y1, Y2, and Y3is tyrosine substituted with - SO3H. In some embodiments, at least two of Y1, Y2, and Y3is tyrosine substituted with -SO3H. In some embodiments, at least one of Y1, Y2, and Y3is tyrosine substituted with -SO3H. In some embodiments, Y1, Y2, and Y3are each tyrosine substituted with -SO3H.

[0083] In certain embodiments, at least one of Y1, Y2, and Y3is phenylglycine substituted with - SO3H, -CH2SO3H, -CF2SO3H, -CO2H, -CONH2, -NHSO2CH3, -SO2NH2, or -CH2PO3H. In certain embodiments, at least two of Y1, Y2, and Y3are phenylglycine substituted with -SO3H, - CH2SO3H, -CF2SO3H, -CO2H, -CONH2, -NHSO2CH3, -SO2NH2, or -CH2PO3H. In certain embodiments, Y1, Y2, and Y3are phenylglycine substituted with -SO3H, -CH2SO3H, -CF2SO3H, -CO2H, -CONH2, -NHSO2CH3, -SO2NH2, or -CH2PO3H.

[0084] In certain embodiments, Y1, Y2, and Y3are each independently tyrosine, phenylalanine, or phenylglycine, and wherein Y1, Y2, and Y3are each independently substituted with -SO3Ry, -

[0022] 21 / 89#14461419v1 CH2SO3Ry, or -CF2SO3Ry, wherein each instance of Ryis independently optionally substituted C1-6alkyl or optionally substituted C6-10aryl. In certain embodiments, Y1, Y2, and Y3are each independently phenylalanine substituted with -SO3Ry, -CH2SO3Ry, or -CF2SO3Ry, wherein each instance of Ryis independently optionally substituted C1-6 alkyl or optionally substituted C6-10 aryl. In certain embodiments, Y1, Y2, and Y3are each independently phenylalanine substituted with -CH2SO3Ry, wherein each instance of Ryis independently optionally substituted C1-6alkyl or optionally substituted C6-10 aryl.

[0085] In some embodiments, W1is threonine. In certain embodiments, W1is serine.

[0086] In certain embodiments, each glycopeptide is independently conjugated to the saccharide or polysaccharide via click chemistry.

[0087] In some embodiments, each glycopeptide is independently conjugated to the saccharide or polysaccharide via a linker, L2. In certain embodiments, L2comprises a substituted or unsubstituted aryl group. In certain embodiments, L2comprises a substituted or unsubstituted aliphatic group. In certain embodiments, L2comprises a substituted or unsubstituted phenyl group. In certain embodiments, L2has the structure: .

[0088] In certain embodiments, L2comprises a substituted or unsubstituted heteroaryl group. In certain embodiments, L2comprises a heteroaryl moiety. In some embodiments, each L2independently comprises a triazole. In certain embodiments, L2independently comprises a 1,2,3- triazole. In some embodiments, each L2is independently comprises one of the following structures:

[0023] 22 / 89#14461419v1; or.

[0089] In some embodiments, the saccharide or polysaccharide comprises one or more sugars selected from the group consisting of: 2-(acetylamino)-2-deoxy-galactose, galactose, 2- (acetylamino)-2-deoxy-glucose, fucose, and 5-acetamido-3,5-dideoxy-glycero-galacto-2- nonulosonic acid.

[0090] In certain embodiments, the saccharide or polysaccharide comprises one or more sugars, e.g., two or more, or three or more sugars. In certain embodiments, the polysaccharide comprises 2, 3, or 4 sugars. In certain embodiments, the sugars are selected from the group consisting of: 2-(acetylamino)-2-deoxy-galactose, galactose, 2-(acetylamino)-2-deoxy-glucose, fucose, and 5-acetamido-3,5-dideoxy-glycero-galacto-2-nonulosonic acid. In a particular embodiment, the polysaccharide is sialyl Lewis X. In another particular embodiment, the polysaccharide is sialyl Lewis X. In certain embodiments, the polysaccharide is sialyl Lewis X or sialyl Lewis A.

[0091] In some embodiments, the polysaccharide comprises a radical S1: wherein L2is bonded to the anomeric oxygen of S1.

[0092] In some embodiments, the polysaccharide further comprises an α 1-3 bond between S1and a radical

[0093] In certain embodiments, the polysaccharide further comprises a β 1-4 bond between S1and a radical

[0094] In some embodiments, the polysaccharide further comprises a β 1-3 bond between S3anda radical

[0024] 23 / 89#14461419v1

[0095] In certain embodiments, the polysaccharide is of the formula: .

[0096] In some embodiments, X1, X2, X3, X4, X5, X6, and X7are each independently E, D, L, or F. In certain embodiments, X1, X2, X3, X4, X6, and X7are each independently E, D, or L.

[0097] As described herein, L1is a linker. In certain embodiments, L1comprises optionally substituted alkylene, optionally substituted heteroalkylene, optionally substituted haloalkylene, optionally substituted alkenylene, optionally substituted alkynylene, optionally substituted carbocyclylene, optionally substituted heterocyclylene, optionally substituted arylene, optionally substituted heteroarylene, optionally substituted acylene, or any combination thereof.

[0098] In some embodiments, L1comprises optionally substituted arylene or optionally substituted heteroarylene. In certain embodiments, L1comprises optionally substituted phenylene. In some embodiments, L1comprises the formula: , wherein each R1is independently optionally substituted alkylene or optionally substituted heteroalkylene; and R2is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, or a half-life extending moiety. In some embodiments, the half-life extending moiety is an albumin binding moiety.

[0099] In certain embodiments, L1comprises one of the following formulae: ,

[0025] 24 / 89#14461419v1

[0100] In certain embodiments, L1comprises one of the following formulae: , , or .

[0101] In certain embodiments, L1comprises one of the following formulae: , .

[0102] In some embodiments, L1comprises the formula:

[0026] 25 / 89#14461419v1 .

[0103] In certain embodiments, R2is: S, O, or NH. In certain embodiments, R2is: .

[0104] In certain embodiments, R2is: , wherein Z is S, O, or NH. In certain embodiments, R2is: . , wherein R3is polyethylene glycol (PEG) or methoxy-PEG (mPEG).

[0106] In some embodiments, R2is . In some embodiments, R2is . In certain embodiments, R2is , wherein R3is polyethylene glycol (PEG) or methoxy-PEG (mPEG). In some embodiments, R2is

[0027] 26 / 89#14461419v1 , whrein n is about 900. In some embodiments, R2is .

[0107] In some embodiments, wherein R2comprises a fatty acid, a lipid, or PEG. In some embodiments, wherein R2comprises methoxy-PEG (mPEG).

[0108] In certain embodiments, L1comprises one of the following formulae:

[0109] In some embodiments, one or both glycopeptides comprise an N-terminal acetyl moiety. In some embodiments, one glycopeptide comprises an N-terminal acetyl moiety. In some embodiments, both glycopeptides comprise an N-terminal acetyl moiety.

[0110] In certain embodiments, the glycopeptide, or salt thereof, comprises a substituted or unsubstituted aliphatic moiety, or a substituted or unsubstituted heteroaliphatic moiety. In certain embodiments, the aliphatic moiety is a substituted or unsubstituted alkyl moiety. In certain particular embodiments, the aliphatic moiety is a substituted or unsubstituted C6-C20 alkyl moiety. In certain embodiments, the aliphatic moiety is a fatty acid radical. In certain embodiments, the aliphatic moiety is palymitoyl.

[0111] In certain embodiments the heteroaliphatic moiety is polyethylene glycol (PEG). The PEG moiety may have 1-10000 repeat units. In certain embodiments, the PEG moiety has 1-10 repeat units, 10-100 repeat units, 100-1000 repeat units, 500-1000 repeat units, 800-1000 repeat units, 1000-3000 repeat units, 3000-6000 repeat units, 4000-8000 repeat units, or 6000-10000 repeat units.

[0112] In certain embodiments, the conjugate comprises at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the amino acid sequence Ac-EY1EY2LDY3DFLZ1EW1EPLK-L1- KLPEW1EZ1LFDY3DLY2EY1E-Ac (SEQ ID NO: 17).

[0113] In certain embodiments, the conjugate comprises the amino acid sequence: Ac-EY1EY2LDY3DFLZ1EW1EPLK-L1-KLPEW1EZ1LFDY3DLY2EY1E-Ac (SEQ ID NO: 17), wherein: W1is threonine conjugated to a polysaccharide; and Y1, Y2, and Y3are each independently phenylalanine substituted with -CH2SO3H.

[0028] 27 / 89#14461419v1

[0114] In certain embodiments, the conjugate comprises the amino acid sequence: Ac-EY1EY2LDY3DFLZ1EW1EPLK-L1-KLPEW1EZ1LFDY3DLY2EY1E-Ac (SEQ ID NO: 17), wherein: W1is threonine conjugated to a polysaccharide via a linker L2; are each independently phenylalanine substituted with -CH2SO3H.

[0115] In certain embodiments, the conjugate comprises the amino acid sequence: Ac-EY1EY2LDY3DFLZ1EW1EPLK-L1-KLPEW1EZ1LFDY3DLY2EY1E-Ac (SEQ ID NO: 17), wherein: W1is threonine conjugated to a polysaccharide via a linker L2;

[0116] In certain embodiments, the conjugate comprises the amino acid sequence: Ac- EY1EY2LDY3DFLZ1EW1EPLK-L1-KLPEW1EZ1LFDY3DLY2EY1E-Ac (SEQ ID NO: 17), wherein: W1is threonine conjugated to a polysaccharide; Y1, Y2, and Y3are each independently phenylalanine substituted certain embodiments, the conjugate comprises the amino acid sequence: Ac-EY1EY2LDY3DFLZ1EW1EPLK-L1-

[0029] 28 / 89#14461419v1 KLPEW1EZ1LFDY3DLY2EY1E-Ac (SEQ ID NO: 17), wherein: W1is threonine conjugated to a polysaccharide; Y1, Y2, and Y3are each independently phenylalanine substituted with - conjugate comprises the amino acid sequence: Ac-EY1EY2LDY3DFLZ1EW1EPLK-L1-KLPEW1EZ1LFDY3DLY2EY1E-Ac (SEQ ID NO: 17), wherein: W1is threonine conjugated to a polysaccharide; Y1, Y2, and Y3are each independently phenylalanine substituted with -CH2SO3H; and L1is .

[0117] In some embodiments, the conjugate is selected from the group consisting of: (CG4_KL1),

[0030] 29 / 89#14461419v1 O HO OO HOH NNO O N O HO HNOH HN NH O O O NO HNSN NO O N HO OH HO O NH OH Ac S NHAc NHOHHN O O SOH CO O OH OHOOH O O NH S NHHOOOHO OH O O OH HN HN OH HO OH O OH O O O O O SOH O NH O NH NH HO OH O SO HO O HOC H HN O HOOO N HOO HO O OH H N O AcHN OH H O HO OH OS O OH HN N HO OH HN HN O O Ac HOHOO H OO H NH HNONNO O N N N O NH N N OH OH O O HO O N OH OO HOHN HN O HOS O N O HOSNH OH HN O N HO O O HO (CG4_KL2),

[0031] 30 / 89#14461419v1SO3HOOHHO H O N OH O N O Ac N O O H NH OH HN H HO OH O O NHSO3HCOH O OH2NHO NH HO OH S NH O OH S OH3HN O HO O HO OSO O O O O HN HO HO HO S O NH AcHN O O OH HN O HN HN O O NH O O ONHN O N O O NH OH N N ONNN O O N HN O OH HOOH N O O HN HO O O O NHAc O NHH NOO OH NH NH O O HOC OH O O HO ONHO OHOOOOH O HN HO OH HN HH2OO OH HO O O Ac OH N O OHO3SHONH NH OHOO N N N HO H O N O O O OH HN HN HO NH O HO NH HO3SOHO3SO HO (CG4_KL3), and pharmaceutically acceptable salts thereof.

[0032] 31 / 89#14461419v1

[0118] In some embodiments, the conjugate is: , or a pharmaceutically acceptable salt thereof.

[0119] In some embodiments, the conjugate is: ,

[0033] 32 / 89#14461419v1 or a pharmaceutically acceptable salt thereof.

[0120] In some embodiments, the conjugate is: SO H or a pharmaceutically acceptable salt thereof.

[0034] 33 / 89#14461419v1

[0121] In some embodiments, the conjugate is: (IPBA-dimer), or a pharmaceutically acceptable salt thereof.

[0035] 34 / 89#14461419v1

[0122] In some embodiments, the conjugate is selected from the group consisting of: ,

[0036] 35 / 89#14461419v1 OH OH OH O OH COH OH HOOOH HNO O O NAcHOHO O AcHN O OH SOH OHNNN HO H O O NS SNH O HN O OOSOH SOH O O HO O OOH O OH OO N NH N H O H O N H O H H H H N NN OO O N N N N N N NNH HN O H O H O N O H O H O H O N OH H HN O HO O HO O HO O HO O O NH SOH O O HN HOS O NH OH O Ac HN HOS NH OH O O HO OH N HO O COH O HN O HOS OH O O HO N HO OH HO HO O O O O O OH HNAcHNOHO N O O NH O O N N HN ON O OH HN O OH O O OHO NO NH , OH CO OH OH OH HO OH H O OOH O O O Ac NO HOOHAcHN NNO N OH OHHO NOHO H O O O SOH SOH O O OOO N O H O H O H O HH O OHHNH H N HN N N N N O N NN N OO N N N HN H O H H O H H H O N OH O NH O O S O HO O HO O HO O O SOH S HN S OH OH COH OH OH OH HOOOOO H O O O HNAc NHOOHO AcHN NNO N OH OOHHO O NHOHO O SOH SOH O O O O N O H O H O H OOHH O OHNH H N H N N N N N NN N OO N N N HN H H H H H H O O O O O N OH O NH O HO O HO O HO O O SOH ,

[0037] 36 / 89#14461419v1 H O c O A H N O O N NON N HNH O O O H O ON HO HH O O O O N HNH c HOO O A O OH NO N O H O H H O H O O O H O H O H O O C I O H O O H H OH Nc A O H ,

[0038] 37 / 89#14461419v1 H O c A NHO H H O O H O C O O H H O O H O O O H O H O H O O c O H A H NOO H O O H ONNN N H O N O O N H OHO HH NO O O ON HO O O N N H H OH NH O O O S NHO H OH NOH O O SN HO HNH O H O O SN HO HOH O N O O OH NO H N O O ONH O H O NN HN H H O N H HOS O O OHH NS H N O O O ONH S S O H ONN HHOHNHH O S N O O S H O O N HHH NO O NHO O N H N c A O H N O O N N NONH N H O O O H O ON HO H H O O O O N H Hc H N O O A O O O O O H O H N H O H O O O H O O H O H O O C O H O O H H OH Nc A O H and pharmaceutically acceptable salts thereof, wherein n is 1-1000 (e.g., about 900).

[0039] 38 / 89#14461419v1

[0123] In certain embodiments, the conjugate comprises at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the amino acid sequence LPEW1EZ1LFDY3DLY2EY1EK-L1- KY1EY2LDY3DFLZ1EW1EPL (SEQ ID NO: 18).

[0124] In certain embodiments, the conjugate comprises the amino acid sequence: LPEW1EZ1LFDY3DLY2EY1EK-L1-KY1EY2LDY3DFLZ1EW1EPL (SEQ ID NO: 18), wherein: W1is threonine conjugated to a polysaccharide; and Y1, Y2, and Y3are each independently phenylalanine substituted with -CH2SO3H.

[0125] In certain embodiments, the conjugate comprises the amino acid sequence: LPEW1EZ1LFDY3DLY2EY1EK-L1-KY1EY2LDY3DFLZ1EW1EPL (SEQ ID NO: 18), wherein: W1is threonine conjugated to a polysaccharide via a linker L2; Y1, Y2, and Y3are each independently phenylalanine substituted with -CH2SO3H.

[0126] In certain embodiments, the conjugate comprises the amino acid sequence: LPEW1EZ1LFDY3DLY2EY1EK-L1-KY1EY2LDY3DFLZ1EW1EPL (SEQ ID NO: 18), wherein: W1is threonine conjugated to a polysaccharide via a linker L2; Y1, Y2, and Y3are each independently phenylalanine substituted with -CH2SO3H; and L1

[0040] 39 / 89#14461419v1

[0127] In certain embodiments, the conjugate comprises the amino acid sequence: LPEW1EZ1LFDY3DLY2EY1EK-L1-KY1EY2LDY3DFLZ1EW1EPL (SEQ ID NO: 18), wherein: W1is threonine conjugated to a polysaccharide via a linker L2; independently phenylalanine substituted with -CH2SO3H; and L1

[0128] In certain embodiments, the conjugate comprises the amino acid sequence: LPEW1EZ1LFDY3DLY2EY1EK-L1-KY1EY2LDY3DFLZ1EW1EPL (SEQ ID NO: 18), wherein: W1is threonine conjugated to a polysaccharide via a linker L2; Y1, Y2, and Y3are each independently phenylalanine substituted with -CH2SO3H; and L1

[0129] In certain embodiments, the conjugate comprises the amino acid sequence: LPEW1EZ1LFDY3DLY2EY1EK-L1-KY1EY2LDY3DFLZ1EW1EPL (SEQ ID NO: 18), wherein: W1is threonine conjugated to a polysaccharide via a linker L2; Y1, Y2, and Y3are each independently phenylalanine substituted with - CH2SO3H; and L140 / 89#14461419v1is .

[0130] In some embodiments, the conjugate is selected from the group consisting of: (G4_KL1),

[0041] 41 / 89#14461419v1 OH OH OH OH COH OH HOOOOH NNO O O HAcO HOOHAcHN O OH SOH OHNNN HO H O O NS SNH O HN O OOSOH SOH O O HO O O O O OOH O OH OO N NH H N NH H H H H H O N N N N N NN N OO N N N H HN O H H H H H N OH O NH O O O O O HN O HO O HO O HO O O HO O NH SOH O O HN HOS O NH OH O Ac HN HOS NH OH O H OH O O N HO O COH O HN O HOS OH O O HO N HO OH HO HO O O O O O OH HNAcHNOHO N O O NH O O N HN ON N O HN O OH OH O O OHO NO NH (G4_KL2), OH OH OH OH COH OH HOOOOH O O O Ac NO HOOHAcHN NNO N OH OHHO NHOHO O O O SOH SOH O O O O O OOH O OH OO N NH H N HN H H H H H N N N NNO N NN OO N N N H HN H O H H H H N OH O NH O O O O O HO S O HO O HO O O SOH S H N OH S OH COH OH OH HO OHOOOO H O O N O HAcO N HOOHAcHN NNO N OH OOHHO OHO NH O O SOH SOH O O O O N O H O H O H OON HH O OHHNH H N N N NN ON N N NNO N H HN H O N O H O H O H O H O N OH H O HO O HO O HO O O SOH (G4_KL3),

[0042] 42 / 89#14461419v1 and pharmaceutically acceptable salts thereof.

[0043] 43 / 89#14461419v1

[0131] In some embodiments, the conjugate is: , or a pharmaceutically acceptable salt thereof.

[0132] In some embodiments, the conjugate is:

[0044] 44 / 89#14461419v1 H O cA NHO H H O O H O C O O H H O O H O O H O H O O H O O c O H A H NOO H O O H ONNN N H O N O H OONHO HH NO O O ON HO O O N N H H OH NH O O O S NHO H OH NOH O O SN HO HNH O H O O SN HO O H O HNO O OH NO H N O O ONH O H O NN HN H O H O HNH S O O OHH NS H N ONH O O O S S O H O N HN HS N O O HNHH O O S H O O N O HHH NO NHO O N H N c A O H N O O N N NNONH H O O O H O ON HO H H O O N O O H Hc HNOO A O O O O O O H N H H O O H O O H O O H O H O O C O H O O H H OH Nc A O H (P-dimer), or a pharmaceutically acceptable salt thereof.

[0045] 45 / 89#14461419v1

[0133] In some embodiments, the conjugate is: or a pharmaceutically acceptable salt thereof.

[0046] 46 / 89#14461419v1

[0134] In some embodiments, the conjugate is: or a pharmaceutically acceptable salt thereof.

[0135] In some embodiments, the compound is a PSGL-1 mimic. In some embodiments, the compound comprises a PSGL-1 mimic. In some embodiments, the compound binds and / or inhibits PSGL-1 receptors. In some embodiments, the compound binds and / or inhibits P- selectin. In some embodiments, the compound binds and / or inhibits L-selectin. In some embodiments, the compound binds and / or inhibits E-selectin. Pharmaceutical Compositions, Kits, and Administration

[0136] The present disclosure provides pharmaceutical compositions comprising a conjugate as disclosed herein, or a salt (e.g., a pharmaceutically acceptable salt) thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a conjugate as disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0137] In certain embodiments, the compound (i.e., conjugate) described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the effective amount is an amount

[0047] 47 / 89#14461419v1 effective for inhibiting the activity (e.g., aberrant activity, such as increased activity) of an enzyme (e.g., P-selectin) in a subject or cell.

[0138] In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile.

[0139] In certain embodiments, the cell is present in vitro. In certain embodiments, the cell is present in vivo.

[0140] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmaceutics. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0141] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one- half or one-third of such a dosage.

[0142] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0143] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering

[0048] 48 / 89#14461419v1 agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0144] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0145] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0146] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0147] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0148] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and

[0049] 49 / 89#14461419v1 the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0149] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject.

[0150] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses).

[0151] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof, and / or in inhibiting the activity of a protein kinase in a subject or cell), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a

[0050] 50 / 89#14461419v1 pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects.

[0152] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease (e.g., proliferative disease, hematological disease, neurological disease, painful condition, psychiatric disorder, or metabolic disorder). Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or composition or administered separately in different doses or compositions. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

[0153] The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain- relieving agents, anesthetics, anti–coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti–pyretics, hormones, and prostaglandins. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional

[0051] 51 / 89#14461419v1 pharmaceutical agent is an anti-cancer agent. In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain embodiments, the additional pharmaceutical agent is a binder or inhibitor of a protein kinase. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, and other agents that promote differentiation. In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, transplantation (e.g., stem cell transplantation, bone marrow transplantation), immunotherapy, and chemotherapy.

[0154] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and / or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form. In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. Methods of Treatment and Uses

[0155] In one aspect, provided herein are methods comprising administering to a subject a conjugate, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition described herein.

[0156] In another aspect, provided are methods of inhibiting P-selectin binding to PSGL-1, comprising contacting the P-selectin with a conjugate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, described herein.

[0157] In one aspect, provided herein are methods of treating or preventing cardiovascular disease, atherosclerosis, atherosclerotic lesions, thrombus formation, thromboembolism, stroke,

[0052] 52 / 89#14461419v1 sickle cell disease, proliferative disease, metabolic syndrome, ischemia reperfusion injury, or myocardial infarction in a subject in need thereof, comprising administering to the subject an effective amount of a conjugate, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition of described herein.

[0158] In some embodiments, provided are methods of inhibiting P-selectin, L-selectin, and / or E- selectin. In some embodiments, provided is a method of inhibiting PSGL-1-receptor interactions.

[0159] In some embodiments, a subject has or is suspected of having a disease or disorder selected from atherosclerotic disease, coronary artery disease, stable angina, coronary bypass surgery, stroke, thrombosis or thromboembolism, peripheral arterial disease, myocardial ischemia, myocardial infarction, atrial fibrillation (AF), aneurysm, pain, fever, inflammation, heparin-induced thrombocytopenia, Hermansky-Pudlak syndrome, Gray Platelet Syndrome, and impaired platelet function due to myelodysplastic syndrome.

[0160] In some embodiments, the subject is at risk of, exhibiting symptoms of, or diagnosed with atherosclerosis, atherosclerotic lesions, thrombus formation, thromboembolism, stroke, or myocardial infarction.

[0161] In certain embodiments, the subject has an increased risk of bleeding relative to that of a healthy adult. In some embodiments, the subject has a history of bleeding. In certain embodiments, the subject has a history of abnormal liver or kidney function or has increased fall risk. In some embodiments, the thromboembolism is venous thromboembolism (VTE). In certain embodiments, the VTE is cancer-associated.

[0162] In another aspect, provided are methods of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a conjugate, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition of the present disclosure.

[0163] In one aspect, provided are methods of treating thromboprophylaxis, comprising administering to a subject diagnosed with cancer an effective amount of a conjugate, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition described herein.

[0164] In another aspect, provided herein are methods of treating or preventing allergy or lung disease in a subject in need thereof, comprising administering to the subject an effective amount of a conjugate, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition of the present disclosure.

[0165] In some embodiments, the subject is at risk of, exhibiting symptoms of, or diagnosed with asthma, bronchitis, emphysema, or chronic obstructive pulmonary disease (COPD).

[0053] 53 / 89#14461419v1

[0166] In one aspect, provided herein are conjugates, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions described herein, for use in any method described herein

[0167] In another aspect, provided are uses of conjugates described herein, and pharmaceutically acceptable salts thereof, and pharmaceutical compositions described herein, in the preparation of medicaments.

[0168] In some embodiments, the compounds provided herein may be used as imaging agents. In certain embodiments, the imaging agent may be used to identify coronary plaque. Methods of Preparation

[0169] In another aspect, provided herein is a method of making a glycopeptide conjugate, comprising reacting an oligosaccharide group comprising a first reactive moiety, with a peptide conjugate comprising a second reactive moiety, to obtain the glycopeptide conjugate, or a salt thereof; wherein the first reactive moiety and the second reactive moiety react to form a heterocyclic moiety. In certain embodiments, the heterocyclic moiety comprises a triazole. In certain embodiments, the heterocyclic moiety comprises a dihydropyridazine.

[0170] In some embodiments, the first reactive moiety comprises an azide, an alkyne, or a strained alkene. In a particular embodiment, the first reactive moiety comprises an azide. In another particular embodiment, the first reactive moiety comprises an alkyne. In another particular embodiment, the first reactive moiety comprises a strained alkene.

[0171] In certain embodiments, the oligosaccharide group has the structure: , or a salt thereof.

[0172] In some embodiments, the second reactive moiety comprises an azide, an alkyne, or a strained alkene. In a particular embodiment, the second reactive moiety comprises an azide. In another particular embodiment, the second reactive moiety comprises an alkyne. In another particular embodiment, the second reactive moiety comprises a strained alkene.

[0054] 54 / 89#14461419v1

[0173] In certain embodiments, the peptide conjugate has the structure: ,

[0055] 55 / 89#14461419v1 , HO O NH O O O SOH SOH O O HN O H O H O OOH O OH OO N NH N H H H H O N N N NNNN OO N N N N H HN H O H O H O H O H O N OH O NH S O HO O HO O HO O O S SOH HN S O HN O HO O NH O O SOH SOH O O O O OOH O OH OO N NH N H H H O H H H N N N NNN N NN OO N N HN H O N O H O H O H H H O O N OH H O HO O HO O HO O O SOH ,

[0056] 56 / 89#14461419v1 O OH OON HOHNO O OO HNOH NH NH OH O O O O O O NHO HNSOH HN O NH N NH HN O NH NH O SOH O O NH O NH HO O O OHOOH N HN H N HN O NH O O OH O O NH O O SOH HO O NH O HN O HN O O OH NH N O O HOS O HN HN O HO HOS O HN O NHO NHOO HNO H OO H NH O N N N H N O O H O O HO HO OH O HOS , O HO OO HOH NNO O N O HO HNOH HN NH O O OO HNO S N NH OH HN S O O SOH O O S NH NH O HN HN OH O O O O O SOH H NH NH N O SOH HO HN O O N H O OH H N O HOS O NH OH HN O HN O O HO OOO H OO H O HN N N NH O NH NH N O H O O O HOS HOO N HO O OH HO O N HN N O H O NH O HOS N HN O HO O O HO , or

[0057] 57 / 89#14461419v1 SO H OOHHO H O N O N N O H O H O HN O NH SO H O H N HO NH S NH O S O HO S HN O O O HN HO HO S O NH O O HN HN HN O O NH O ONHN O O O NH N O HN HOO OH N O O HN O NHOO OH NH H N NH O O O O HO ON O O HN O OH HO O N O HO S O NH OHONHHON O HO N N O N OH O H O HN O HN HO NH O HO NH HO S HO S O O HO , or a salt thereof. EXAMPLES

[0174] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting in their scope. Example 1. Inhibition of P-selectin-Fc chimeras binding to human and murine leukocytes

[0175] Flow cytometry was used to quantify binding inhibition of P-selectin-Fc chimeras to human and murine leukocytes. Whole mouse blood was collected via cardiac puncture in 3.2% sodium citrate and human blood was collected from healthy adult volunteers using BD Vacutainer® sodium citrate tubes. Leukocytes were isolated by centrifugation and red blood cells lysed using red blood cell (RBC) lysis buffer (eBioscienceTM). Members of a focused library of dimeric glycosulfopeptides (GSPs) were initially screened for their ability to block the binding of a murine P-selectin-Fc chimera to murine monocytes and neutrophils using whole mouse blood. A total of 3 x 105leukocytes were incubated with increasing concentrations of

[0058] 58 / 89#14461419v1 dimeric GSPs (0-10 µM) and murine P-selectin-Fc chimera (2 μg; R&D Systems®) followed by phycoerythrin (PE)-conjugated anti-Fc antibody (1:100; Life Technologies®) at 4°C.

[0176] The most potent compounds were subsequently evaluated for their capacity to inhibit binding of human P-selectin-Fc chimera to human monocytes and neutrophils using human whole blood and compared to the inhibitory activity of the monomeric glycosulfopeptide, G4, or its pegylated derivative, P-G4. Leukocytes were incubated with increasing concentrations of dimeric GSPs (0-10 µM), G4 (0-100 µM), or P-G4 (0-100 µM), and then reacted with human P- selectin-Fc chimera (2 μg; R&D Systems®) which was pre-reacted with PE-conjugated anti-Fc antibody (0.05 μg; Life Technologies®). Monocytes and neutrophils were discerned through inclusion of monocyte marker anti-human CD14-Pacific Blue (BD PharmigenTM) or anti-mouse CD11b-eFluor® 450 (eBioscienceTM).

[0177] The interaction of P-selectin with human and murine monocytes and neutrophils was analyzed by flow cytometry (CytoFlex LX, Beckman Coulter®) and quantified as percent inhibition using FlowJo. Inhibition experiments were conducted in quadruplicate, and data are shown as mean ± SEM. Example 2. Inhibition of P-selectin-Fc chimera binding to primary mouse monocytes and neutrophils

[0178] CG4_KL1 blocked P-selectin-Fc chimera binding to murine monocytes and neutrophils with an IC50 of 1.47 µM and 1.20 µM, respectively (FIG.1A). CG4_KL2 blocked P-selectin-Fc chimera binding to murine monocytes and neutrophils with an IC50of 0.70 µM and 0.99 µM, respectively (FIG. 1B). CG4_KL3 blocked P-selectin-Fc chimera binding to murine monocytes and neutrophils with an IC50 of 8.64 µM and 12.98 µM, respectively (FIG. 1C). G4_KL1 blocked P-selectin-Fc chimera binding to murine monocytes and neutrophils with an IC50of 2.81 µM and 4.05 µM, respectively (FIG.1D). G4_KL2 blocked P-selectin-Fc chimera binding to murine monocytes and neutrophils with an IC50 of 7.49 µM and 10.79 µM, respectively (FIG. 1E). G4_KL3 blocked P-selectin-Fc chimera binding to murine monocytes and neutrophils with an IC50of 8.68 µM and 9.66 µM, respectively (FIG.1F). Example 3. Inhibition of P-selectin-Fc chimera binding to primary human monocytes and neutrophils

[0179] CG4_KL1 blocked P-selectin-Fc chimera binding to human monocytes and neutrophils with an IC50of 110 nM and 303 nM, respectively (FIG.2A). CG4_KL2 blocked P-selectin-Fc chimera binding to human monocytes and neutrophils with an IC50 of 49 nM and 125 nM, respectively (FIG.2B). In comparison to P-G4, CG4_KL2 displayed 108-fold and 117-fold greater inhibitory potency in blocking P-selectin-Fc chimera binding to human monocytes and

[0059] 59 / 89#14461419v1 neutrophils, respectively (FIG.2C). In comparison to G4, CG4_KL2 displayed 163-fold and 149-fold greater inhibitory potency in blocking P-selectin-Fc chimera binding to human monocytes and neutrophils, respectively (FIG.2D). Example 4. Assessment of platelet-leukocyte aggregation in vitro.

[0180] Platelet-leukocyte aggregates were quantified in whole blood using flow cytometry (CytoFlex LX, Beckman Coulter®). Whole human and mouse blood was collected into citrate coated tubes, incubated with increasing concentrations (10-100 µM) of CG4_KL1 or CG4_KL2 at room temperature, and stimulated with thrombin receptor-activating peptide (human PAR1-activating peptide 100 µM; mouse PAR4-activating peptide 50 µM) to induce platelet P-selectin expression. Platelet–leukocyte aggregates were quantified by two-color flow cytometry by incubating human samples with anti-human CD45-APC (BD PharmigenTM) and anti-human CD42a-PE (BD PharmigenTM) and mouse samples with anti-mouse CD45-APC (eBioscienceTM) and anti-mouse CD41-FITC (BD PharmigenTM). Human CD45+ monocytes and neutrophils were discerned through characteristic side scatter. Mouse CD45+ leukocyte populations were gated using anti-CD11b-eFluor® 450 (eBioscienceTM) and anti-Ly-6G-PE (BD PharmigenTM). Data were quantified as a percentage (%) of platelet positive platelet-monocyte or platelet-leukocyte aggregates in saline vehicle. Inhibition experiments were conducted at least in triplicate, and data shown as mean ± SEM. Example 5. Assessment of dimeric CG4_KL2 Glycosulfopeptide P-selectin inhibitor

[0181] Synthesis of a PEGylated-dimeric CG4_KL2 glycosulfopeptide (P-dimer). To enhance the circulating half-life (t1 / 2) of the dimeric glycosulfopeptide CG4_KL2, the conjugation of CG4_KL2 to 40 kDa methoxy polyethylene glycol succinimidyl valerate (mPEG-SVA) was performed in DMF. A total of 8 mg of the dimeric glycosulfopeptide was dissolved in 2 mL DMF and mPEG-SVA (5 equiv.) added. Subsequently, 0.2 mL DIPEA was slowly added and shaken for 22 hours at 25°C. The reaction was quenched using acetic acid and the solvent was removed by vacuum. Crude material was purified using ion-exchange chromatography to afford the final product, PEGylated-dimeric CG4_KL2 glycosulfopeptide (P-dimer), in 72% yield. The final compound was confirmed by MALDI-TOF MS. Purity was assessed using analytical RP- HPLC.

[0182] Ion-Exchange purification protocol. The crude reaction mixture was first dissolved in 50 mL of water and lyophilized to ensure complete removal of residual DMF. The resulting powder was reconstituted in 20 mM Tris buffer (20 mg / mL, pH 7.0-8.0) to prepare for purification. The sample was loaded onto a Cytiva HiTrap™ Q HP anion-exchange chromatography column at a flow rate of 2 mL / minute. Following loading, the column was washed with three column

[0060] 60 / 89#14461419v1 volumes of 25 mL each of 20 mM Tris buffer to remove excess PEG40K. The wash fractions were monitored by UV-vis spectroscopy, and little to no absorbance was observed at 210 nm, indicating efficient clearance of unreacted PEG.

[0183] Elution of the desired product was achieved with two 25 mL fractions of 1 M NaCl in 20 mM Tris, applied at a flow rate of 2 mL / minute. The pooled eluate was concentrated using centrifugal spin filters with a 10 kDa molecular weight cut-off, spun at 4000 × g at room temperature for 30 minutes. This step removed unreacted dimer and other low–molecular weight impurities, which could be collected for potential recycling. For desalting, 2.5 mL aliquots of the concentrated eluate were applied sequentially to a pre-equilibrated desalting column. The product was eluted in HPLC-grade water to a final volume of 3.5 mL. The purified product was then lyophilized to yield a white solid.

[0184] A PEGylated-dimeric glycosulfopeptide (P-dimer) inhibited P-selectin binding to PSGL-1. Flow cytometry was used to evaluate the ability of P-dimer to block binding of P-selectin-Fc chimera to murine leukocytes. Recombinant species-specific P-selectin-Fc chimera (3 μg / mL) was incubated with murine leukocytes in the presence of P-dimer (0 - 30 µM). Binding of P- selectin was detected with phycoerythrin (PE)-conjugated anti-Fc antibody and quantified as mean fluorescent intensity and plotted as percent inhibition. P-dimer inhibited P-selectin binding to murine leukocytes in a dose-dependent manner comparable to the non-pegylated CG4_KL2 glycosulfopeptide dimer (FIG.6). P-dimer (PEGylated-CG4_KL2) blocked P- selectin binding to murine monocytes (IC500.7851 µM), and murine neutrophils (IC500.7152 µM). The non-pegylated dimer (CG4_KL2) blocked P-selectin binding to murine monocytes (IC500.7336 µM), and murine neutrophils (IC501.010 µM).

[0185] Flow cytometry assay. Whole mouse blood was collected via cardiac puncture in 3.2% sodium citrate using BD Vacutainer® sodium citrate tubes. Leukocytes were isolated by centrifugation and red blood cells lysed using red blood cell (RBC) lysis buffer (eBioscienceTM). A total of 3 x 105leukocytes were incubated with increasing concentrations of P-dimer (0-30 µM) and murine P-selectin-Fc chimera (3 μg / mL; R&D Systems®) followed by phycoerythrin (PE)-conjugated anti-Fc antibody (1:100; Life Technologies®) at 4°C. Monocytes and neutrophils were discerned through inclusion of monocyte marker CD11b-APC (mouse). The interaction of P-selectin with murine monocytes and neutrophils was analyzed by flow cytometry (CytoFlex LX, Beckman Coulter®) and quantified as percent inhibition using FlowJo. Inhibition experiments were conducted in triplicate.

[0186] A PEGylated-dimeric glycosulfopeptide (P-dimer) inhibited venous thrombosis. In seeking a route for patient self-administered dosing, inhibition of venous thrombosis was evaluated in the setting of once daily subcutaneous delivery of P-dimer (FIG.7). Mice received daily

[0061] 61 / 89#14461419v1 subcutaneous dosing of P-dimer (0.4 µmol / kg), the vena cava was injured 4 hours after the fourth dose (76 hours), and the vena cava and thrombus harvested 24 hours after a fifth and final dose (124 hours). A statistically significant reduction in thrombus formation was observed with respect to saline vehicle control.

[0187] Murine model of non-occlusive venous thrombosis. Drug efficacy was evaluated in a preclinical mouse model in which non-occlusive venous thrombosis was induced by electrolytic injury of the inferior vena cava (105). In brief, C57BL / 6 mice (n = 6 / group; 8-12 weeks of age; Jackson Labs, Bar Harbor, ME, USA) were anesthetized with 2% isoflurane and the inferior vena cava approached via a midline laparotomy. Venous side branches were ligated or cauterized, while posterior branches were left patent. A 25-gauge stainless steel needle, attached to a silver-coated copper wire was inserted into the exposed caudal vena cava and positioned against the anterior wall (anode). A second wire was implanted subcutaneously to complete the circuit (cathode) and a 250 µAmps current applied for 15 minutes. Subsequently, the needle was removed and a cotton swab held in gentle contact with the puncture site to prevent bleeding. The vena cava and associated thrombus, immediately below the renal veins to just above the bifurcation, was excised 48 hours after injury for determination of wet thrombus weight. The P- dimer (0.4 µmol / kg) or saline vehicle were administered subcutaneously once daily, with electrolytic injury 4 hours after the fourth dose (100 hours), and the vena cava and associated thrombus excised 24 hours after the fifth dose and final dose (120 hours) for determination of wet thrombus weight.

[0188] Synthesis of an albumin binding dimeric CG4_KL2 glycosulfopeptide P-selectin inhibitor. The incorporation of 4-(p-iodophenyl)butyric acid (IPBA) as an albumin-binding moiety has emerged as a powerful strategy to extend the circulating half-life of peptide therapeutics. By reversibly associating with serum albumin, IPBA-modified peptides exploit the long plasma residence of albumin (~19 days in humans) to remain in circulation longer than their unmodified counterparts. This enhanced blood residence time has been shown across multiple systems, including folate conjugates, integrin-binding peptides, and PSMA-targeted radioligands, to improve pharmacokinetics, increase tumor accumulation, and reduce rapid renal clearance. Compared with other albumin-binding strategies, IPBA confers strong, tunable binding affinity while preserving target selectivity and bioactivity.

[0189] Synthesis of an 4-(p-iodophenyl)butyric acid (IPBA) bearing dimeric N- hydroxysuccinimide (NHS) linker (4g).

[0062] 62 / 89#14461419v1 O O 10) O BocHN BocHN N OH O O NHAc NHAc 4a I O I 1 I O O 1 )O12) N N H OH O OH O 4c O IPBA 4bI O O 13) N H N O O O 4d

[0190] N2-acetyl-N6-(tert-butoxycarbonyl)-L-lysine (1.44 g, 5 mmol) was mixed with EDC (1.44 g, 7.5 mmol) and N-hydroxysuccinimide (1.15 g, 10 mmol) in 10 mL of DMF. The reaction was stirred at room temperature overnight. The product was extracted with ethyl acetate (100 mL, twice) and 100 mL of water. The organic layers were combined, washed with 100 mL of 1N HCl and saturated brine. The product was dried over anhydrous sodium sulfate and ethyl acetate was removed by vacuum. The crude product 4a was used without further purification.

[0191] 4-(p-Iodophenyl)butyric acid (IPBA, 302 mg, 2 mmol) was mixed with EDC (573 mg, 7.5 mmol) and N-hydroxysuccinimide (460 mg, 4 mmol) in 1 mL of DMF. The reaction was stirred at room temperature overnight. The product was extracted with ethyl acetate (100 mL, twice) and 100 mL of water. The organic layers were combined, washed with 100 mL of 1N HCl and saturated brine. The product was dried over anhydrous sodium sulfate and ethyl acetate was removed by vacuum to obtain a white solid 4b. A total of 100 mg of 4b (0.26 mmol) was mixed with 59 mg of 4-(aminomethyl)benzoic aicd (0.39 mmol) in 0.3 mL of DMF with 30 μL of DIPEA. The reaction was agitated on a shaker for 4 hours. The crude reaction was directly purified on RP-HPLC with Method A to give 102 mg of 4c as white solid. Yield 85 mg, 78%. Specifically, the RP-HPLC gradient used for preparative purposes included a solvent A comprised of water with 0.1% TFA and a solvent B consisting of acetonitrile with 0.1% TFA. Method A: 0-2 minutes: 5% B, 2-5 minutes: 5-40% B, 5-16 minutes: 40%-70% B, 16-17 minutes: 70-98% B, 17-18.5 minutes: 98% B, 18.5-20 minutes: 95-5% B. Flow rate: 40 mL / minute.

[0192] Compound 4c (85 mg, 0.2 mmol) was dissolved in 0.5 mL of DMF, to which was added EDC (57 mg, 0.3 mmol) and N-hydroxysuccinimide (46 mg, 0.4 mmol). The reaction was stirred at room temperature overnight. The product was extracted with ethyl acetate (100 mL, twice) and 100 mL of water. The organic layers were combined, washed with 100 mL of 1N

[0063] 63 / 89#14461419v1 HCl and saturated brine. The product was dried over anhydrous sodium sulfate and ethyl acetate was removed by vacuum. The crude product 4d was used without further purification. Yield 97 mg, 93%. MALDI m / z calculated for C22H21IN2O5+[M+H]+: 521.057, found: 521.0861H NMR (400 MHz, CDCl3) δ 8.18 – 8.05 (m, 2H), 7.68 – 7.54 (m, 2H), 7.47 – 7.37 (m, 2H), 7.01 – 6.85 (m, 2H), 5.92 (s, 1H), 4.52 (d, J = 5.6 Hz, 2H), 2.92 (s, 4H), 2.63 (t, J = 7.5 Hz, 2H), 2.26 (q, J = 7.5 Hz, 2H), 2.13 – 1.91 (m, 2H).13C NMR (100 MHz, CDCl3) δ 172.56, 169.52, 169.20, 169.00, 166.95, 161.58, 146.01, 140.98, 137.60, 137.48, 134.02, 131.71, 130.98, 130.60, 128.03, 127.99, 124.28, 91.06, 77.23, 52.01, 43.17, 37.48, 35.51, 34.65, 31.64, 26.74, 25.69, 25.58, 25.46.

[0064] 64 / 89#14461419v1 OO OH o HIN B c N N HN NHAc HN H NHAc 14), 15) 16), 17)O 2a S S HO S S OH HO S S OHO O O O4e 4f OO IH N N HN H NHAc O 18), 19)S O O OS S ON N OOO 4g O

[0193] Compound 2a (106 mg, 0.2 mmol) was treated by 1 mL of neat TFA for 1 hour to remove the Boc protection group. TFA was removed under vacuum and the residual was redissolved in 1 mL of DMF with 0.1 mL of DIPEA, to which was added 4a (115 mg, 0.3 mmol). The reaction was agitated for 4 hours and purified by RP-HPLC with Method A to give intermediate 4e. Yield 60 mg, 46%. MALDI m / z calculated for C30H47N3NaO8S3+[M+Na]+: 696.241, found: 691.1941H NMR (400 MHz, MeOD) δ 7.23 (q, J = 1.6 Hz, 3H), 4.27 (dd, J = 8.6, 5.5 Hz, 1H), 3.75 (d, J = 2.5 Hz, 6H), 3.45 – 3.26 (m, 2H), 3.04 (t, J = 6.8 Hz, 2H), 2.66 (td, J = 7.1, 1.0 Hz, 4H), 2.60 – 2.49 (m, 6H), 2.00 (s, 3H), 1.85 – 1.73 (m, 1H), 1.72 – 1.58 (m, 1H), 1.50 (p, J = 6.6 Hz, 2H), 1.45 (s, 9H), 1.43 – 1.31 (m, 2H).13C NMR (100 MHz, MeOD) δ 174.24, 173.04, 171.92, 139.12, 127.95, 127.92, 53.52, 48.10, 39.71, 38.32, 35.24, 34.86, 34.01, 31.50, 29.98, 29.22, 27.42, 25.83, 22.78, 21.11.

[0194] Compound 4e (30 mg, 45 μmol) was treated by 1 mL of neat TFA for 1 hour to remove the Boc protection group. TFA was removed under vacuum and the residual was redissolved in 0.5 mL of DMF with 50 μL of DIPEA, to which was added 4d (35 mg, 67 μmol). The reaction was agitated for 4 hours and purified by RP-HPLC with Method A to give intermediate 4f. Yield 35 mg, 80%. MALDI m / z calculated for C43H55IN4NaO8S3+[M+Na]+: 1001.212, found: 1001.5401H NMR (400 MHz, MeOD) δ 7.71 – 7.64 (m, 2H), 7.52 – 7.45 (m, 2H), 7.26 (d, J = 8.1 Hz, 2H), 7.09 (s, 2H), 6.86 (d, J = 8.1 Hz, 2H), 4.29 (s, 2H), 4.16 (dd, J = 8.4, 5.7 Hz, 1H), 3.60 (d, J = 11.7 Hz, 6H), 3.31 – 3.12 (m, 4H), 2.59 – 2.33 (m, 12H), 2.15 (t, J = 7.4 Hz, 2H), 1.84 (d, J = 18.6 Hz, 4H), 1.78 – 1.65 (m, 1H), 1.55 (tt, J = 14.3, 6.4 Hz, 2H), 1.32 (tdd, J = 17.6, 6.9, 4.5 Hz, 2H).13C NMR (100 MHz, MeOD) δ 174.26, 139.10, 137.19, 130.38, 127.95, 127.93, 127.20, 127.14, 53.51, 48.25, 48.04, 47.82, 47.62, 47.61, 47.41, 47.40, 47.20, 47.18, 46.98, 46.97, 42.32, 39.25, 38.33, 35.27, 34.90, 34.27, 34.02, 31.47, 30.02, 28.74, 27.04, 25.87, 22.87, 21.14.

[0065] 65 / 89#14461419v1

[0195] Compound 4f (35 mg, 36 μmol) was mixed with EDC (21 mg, 110 μmol) and N- hydroxysuccinimide (16 mg, 140 μmol) in 0.2 mL of DMF. The reaction was agitated at room temperature overnight. The product was extracted with ethyl acetate (50 mL, twice) and 50 mL of water. The organic layers were combined, washed with 50 mL of 1N HCl and saturated brine. The product was dried over anhydrous sodium sulfate and ethyl acetate was removed by vacuum. The product 4g was used without further purification. Yield 38 mg, 91% yield. MALDI m / z calculated for C51H61IN6NaO12S3+[M+Na]+: 1195.245, found: 1195.263.

[0196] A total of 3.0 mg of 4g was mixed with 15 mg of a propargylated peptide (with an amino acid sequence identical to that described in the original provisional patent description) in an eppendorf tube. The mixture was dissolved in 60 μL of DMF with 6 μL of DIPEA. The reaction was placed on a shaker and agitated overnight at room temperature The crude mixture was diluted by 1 mL of acetonitrile / water (1:1) and purified by RP-HPLC with Method C. The RP- HPLC gradient used for preparative purposes included a solvent A comprised of water with 0.1% TFA and a solvent B consisting of acetonitrile with 0.1% TFA where Method C: 0-2 minutes: 5% B, 2-15 minutes: 5-40% B, 15-16 minutes: 40%-63% B, 16-17 minutes: 63-98% B, 17-18.5 minutes: 98% B, 18.5-20 minutes: 95-5% B. Flow rate: 40 mL / minute. The product, an IPBA bearing propargylated peptide dimer, was dried on a lyophilizer to yield 6.0 mg of the propargylated peptide dimer as a white powder (40% yield).

[0197] An IPBA bearing propargylated peptide dimer (1 e.q.) (FIG.9) was mixed with 1M copper sulfate (6 e.q.), 1M sodium ascorbate (8 e.q.) and THPTA (4 e.q.). A total of 2.5 e.q. of the sLex-azide dissolved in DMF was immediately added to the mixture. The reaction was covered by aluminum foil and shaken for 16 hours at room temperature The desired product, an IPBA bearing glycosulfopeptide dimer (IPBA-dimer) (FIG.9), was isolated by prep-HPLC with Method B. The RP-HPLC gradient used for preparative purposes included a solvent A comprised of water with 0.1% TFA and a solvent B consisting of acetonitrile with 0.1% TFA, where Method B: 0-2 minutes: 5% B, 2-5 minutes: 5-30% B, 5-16 minutes: 30%-37% B, 16-17 minutes: 37-98% B, 17-18.5 minutes: 98% B, 18.5-20 minutes: 95-5% B. Flow rate: 40 mL / minute. Product yield 6.3 mg, 81%.

[0198] An IPBA bearing glycosulfopeptide dimer (IPBA-dimer) (FIG.9) inhibits P-selectin binding to PSGL-1. Flow cytometry was used to evaluate the ability of an IPBA-dimer to block binding of P-selectin-Fc chimera to murine leukocytes. Recombinant species-specific P-selectin- Fc chimera (3 μg / mL) was incubated with murine leukocytes in the presence of IPBA-dimer (0 - 30 µM). Binding of P-selectin was detected with phycoerythrin (PE)-conjugated anti-Fc antibody and quantified as mean fluorescent intensity and plotted as percent inhibition. IPBA- dimer inhibited P-selectin binding to murine leukocytes in a dose-dependent manner

[0066] 66 / 89#14461419v1 comparable to the non-pegylated CG4_KL2 glycosulfopeptide dimer (FIG.10). IPBA-dimer blocked P-selectin binding to murine leukocytes, including murine monocytes (IC500.3977 µM), and murine neutrophils (IC501.140 µM). Example 6. Materials and Methods

[0199] General. All reagents were purchased from commercial sources and used as received. For peptide synthesis, Fmoc-Phe(CH2SO3H)-OH was purchased from RSP Amino Acids (Shirley, MA). Fmoc-Thr(propargyl)-OH was synthesized according to a published protocol [cite]. HBTU, N-(3-dimethylaminopropyl)-N’-ethylcarbodiimide hydrochloride (EDC), tris(2- carboxyethyl)phosphine hydrochloride (TCEP), trifluoroacetic acid (TFA), tris(3- hydroxypropyltriazolylmethyl)amine (THPTA), pre-loaded Wang resin and all other Fmoc protected amino acids were purchased from Chem-Impex International (Wood Dale, IL). Benzene-1,3,5-tricarboxylic acid, N-Boc-ethylenediamine, 1,3,5-tris(bromomethyl)benzene, 2- (Boc-amino) ethanethiol, N,N-diisopropylethylamine, diethyl ether (anhydrous), and potassium hydroxide (KOH) were purchased from Sigma-Aldrich.3-Mercaptopropionic acid was purchased from Acros Organics (Thermo-Fisher). N-hydroxysuccinimide (NHS), dichloromethane (DCM), N,N-dimethylformamide (DMF), triethylsilane, and potassium carbonate were purchased from Alfa Aesar (Haverhill, MA). Methanol, ethyl acetate, hexanes, and acetone were purchased from Pharmco-Greenfield Global (Mississauga, ON). Sodium chloride and sodium sulfate were purchased from Fisher Scientific. Reverse phase high performance liquid chromatography (RP-HPLC) was performed using a Waters 2767 Gradient Purification System, equipped with either a C18100 Å preparative (250 x 30 mm, Phenomenex) or analytical (50 x 4.6 mm, Phenomenex) column.

[0200] HPLC methods. The RP-HPLC gradient used for preparative purposes included a solvent (A) comprised of water with 0.1% TFA and a solvent (B) consisting of acetonitrile with 0.1% TFA. Method A: 0-2 minutes: 5% B, 2-5 minutes: 5-40% B, 5-16 minutes: 40%-70% B, 16-17 minutes:70-98% B, 17-18.5 minutes: 98% B, 18.5-20 minutes: 95-5% B. Flow rate: 40 mL / minute. Method B: 0-2 minutes: 5% B, 2-5 minutes: 5-30% B, 5-16 minutes: 30%-37% B, 16-17 minutes:37-98% B, 17-18.5 minutes: 98% B, 18.5-20 minutes: 95-5% B. Flow rate: 40 mL / minute. Method C: 0-2 minutes: 5% B, 2-15 minutes: 5-40% B, 15-16 minutes: 40%-63% B, 16-17 minutes:63-98% B, 17-18.5 minutes: 98% B, 18.5-20 minutes: 95-5% B. Flow rate: 40 mL / minute. Analytical method: 0-2 minutes: 5% B, 2-18 minutes: 5-95% B, 18-20 minutes: 95% B, 20-20.01 minutes: 95-5% B, 20.01-22 minutes: 5% B. Flow rate: 2.5 mL / minute.

[0067] 67 / 89#14461419v1 Scheme S1. Synthetic scheme for KL1 linker

[0201] Synthesis of KL1 linker. Benzene-1,3,5-tricarboxylic acid (1.05 g, 5 mmol), EDC (3.27 g, 16.5 mmol) and NHS (2.3 g, 20 mmol) were dissolved in 10 mL of DMF. The reaction was stirred for 18 hours at room temperature The product was extracted with EtOAc (150 mL, twice) and 150 mL of water. The organic aliquots were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. EtOAc was removed by vacuum to yield 1a as a white solid. The crude product was used without further purification. Yield: 2.6 g, 97%.1H NMR (400 MHz, CDCl3) δ 9.12 (s, 3H), 2.93 (s, 12H).13C NMR (100 MHz, CDCl3) δ 168.46, 159.55, 137.37, 127.71, 25.64. HR-ESI-TOF m / z calculated for C21H15N3NaO12+[M+Na]+: 524.05479, found: 524.37691.

[0202] Compound 1a (0.5 g, 1 mmol) was dissolved in 5 mL of DMF. A total of 160 mg of N- Boc-ethylenediamine was added drop-wise while the solution was stirred at 0°C. A total 0.25 mL of DIPEA was added immediately and the reaction was allowed to stir for 2 hours at room temperature The reaction was quenched by the addition of 100 mL of EtOAc and 100 mL of water. The organic layer was separated from the aqueous layer in a separation funnel. The aqueous layer was then extracted with another 100 mL EtOAc. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. EtOAc was removed under vacuum and the crude mixture was purified by silica gel chromatography. The desired product was eluted by EtOAc / hexanes (3:2) to yield KL1 as a white solid. Yield: 150 mg, 28%.1H NMR (400 MHz, DMSO) δ 9.09 (t, J = 5.7 Hz, 1H), 8.88 (s, 2H), 8.72 (s, 1H), 3.32 (q, J = 5.8 Hz, 2H), 3.13 (q, J = 5.7 Hz, 2H), 2.91 (s, 8H), 1.34 (s, 9H).13C NMR (100 MHz, DMSO) δ 170.47, 163.94, 160.85, 156.19, 137.56, 135.12, 133.15, 126.59, 78.15, 28.66, 26.04, 25.67. HR-ESI-TOF m / z calculated for C24H26N4NaO11+[M+Na]+: 569.14903, found: 569.15348 Scheme S2. Synthetic scheme for KL2 linker

[0068] 68 / 89#14461419v1

[0203] Synthesis of KL2 linker. 2-(Boc-amino)ethanethiol (177 mg, 1 mmol) and 3- mercaptopropionic acid (212 mg, 2 mmol) were dissolved in 1 mL of DMF. This solution was added drop-wise to 1,3,5-tris(bromomethyl)benzene (358 mg, 1 mmol) dissolved in 6 mL of DMF. The mixture was stirred at 0°C. To maintain a reduced and basic condition, a buffer solution was prepared separately in a test tube. TCEP (0.25 g) was dissolved in 2 mL of water and the pH was tuned to ~ pH 7 with 1M KOH. A total of 200 mg of K2CO3was added to generate the final buffer solution, which was added to the reaction drop-wise. The reaction was warmed to room temperature and allowed to proceed for 6 h. The reaction was quenched by the addition of 1 N HCl until pH 2. The product was extracted with EtOAc (200 mL, twice) and 100 mL of water. The organic aliquots were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. EtOAc was removed by vacuum. The crude product was purified by prep-HPLC (Method A). The intermediate 2a is a white solid after lyophilization. Yield: 150 mg, 30%.1H NMR (400 MHz, CD3OD) δ 7.20 (d, J = 1.8 Hz, 3H), 3.73 (s, 4H), 3.72 (s, 2H), 3.35 (s, 4H), 3.18 (t, J = 7.0 Hz, 2H), 2.63 (td, J = 7.0, 1.0 Hz, 4H), 2.55 – 2.42 (m, 6H), 1.43 (s, 9H).13C NMR (100 MHz, cd3od) δ 174.23, 139.18, 139.05, 127.94, 127.87, 48.08, 39.45, 35.19, 34.84, 33.95, 30.50, 27.37, 25.77. HR-ESI-TOF m / z calculated for C22H33NNaO6S3+[M+Na]+: 526.13622, found: 526.13527

[0204] Compound 2a (80 mg, 0.16 mmol), EDC (92 mg, 0.48 mmol) and NHS (74 g, 0.64 mmol) were dissolved in 1 mL of DMF. The reaction was stirred for 18 hours at room temperature The product was extracted with DCM (100 mL, twice) and 100 mL of water. The organic aliquots were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. DCM was removed by vacuum. The crude product was purified by silica gel chromatography. The desired product was eluted by 40% EtOAc in DCM to yield KL2 as a white solid. Yield: 64 mg, 57%.1H NMR (400 MHz, CDCl3) δ 7.19 (s, 3H), 3.74 (s, 4H), 3.69 (s, 2H), 3.24 (t, J = 6.6 Hz, 2H), 2.88 – 2.78 (m, 12H), 2.75 (ddd, J = 8.9, 6.3, 1.9 Hz, 4H), 2.51 (t, J = 6.6 Hz, 2H), 1.43 (d, J = 1.7 Hz, 9H).13C NMR (100 MHz, CDCl3) δ 168.97, 167.07, 139.19, 138.67, 128.32, 128.20, 36.15, 35.45, 31.75, 31.44, 28.40, 25.69, 25.58. HR-ESI-TOF m / z calculated for C30H39KN3O10S3+[M+K]+: 736.14292, found: 736.15422

[0069] 69 / 89#14461419v1NH2NHBoc S Br 5)S6), 7)Br HN S SBr NHBocHN S SNHBocO O O O 3aOH3bOH NHBoc NHBoc S S 8) 9)HN S SNHHN S SNHO O O O O O O O O O ONONOH 3c OH KL3 O O Scheme S3. Synthetic scheme for KL3 linker

[0205] Synthesis of KL3 linker.2-(Boc-amino)ethanethiol (1.48 g, 8.4 mmol) was added drop- wise to 1,3,5-tris(bromomethyl)benzene (1 g, 2.8 mmol) dissolved in 20 mL of DMF while being stirred at 0°C. A buffer solution containing 0.25 g of TCEP (tuned to pH 7.4 with 1M KOH) and 200 mg of K2CO3 was added to the reaction drop-wise. The reaction was warmed to room temperature and allowed to proceed for 16 h. Complete conversion of the starting material was observed. The reaction was quenched by the addition of 200 mL of 0.01 N HCl. The product was extracted by EtOAc (250 mL, twice) and washed with 200 mL of water, and then 200 mL of saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was then removed under vacuum. The crude product 3a was purified by silica gel chromatography, eluted with 25% EtOAc in hexanes. Yield: 1.06 g, 63%.1H NMR (400 MHz, CD3OD) δ 7.20 (s, 3H), 3.72 (s, 6H), 3.18 (t, J = 7.0 Hz, 6H), 2.48 (t, J = 7.0 Hz, 6H), 1.43 (s, 27H).13C NMR (100 MHz, CD3OD) δ 156.88, 139.12, 127.94, 78.70, 39.52, 34.93, 30.59, 27.41. HR-ESI-TOF m / z calculated for C30H51N3NaO6S3+[M+Na]+: 668.28322, found: 668.28327

[0206] Compound 3a (0.4 g, 0.62 mmol) was treated with 2 mL of neat TFA for 0.5 hours at room temperature TFA was removed under vacuum and this process was repeated one more time to remove the Boc protection completely. TFA treated 3a was redissolved in 2 mL of DMF containing 0.3 mL of DIPEA and stirred over ice. Succinic anhydride (124 mg, 1.24 mmol) was dissolved in 1 mL of DMF and added drop-wise to the reaction. The reaction was warmed to room temperature and allowed to proceed for 4 h. DMF and DIPEA were removed under vacuum and the product was purified by prep-HPLC (Method A). Compound 3b was obtained

[0070] 70 / 89#14461419v1 as a white solid after lyophilization. Yield: 140 mg, 41%.1H NMR (400 MHz, CD3OD) δ 7.23 (q, J = 1.6 Hz, 3H), 3.78 (s, 2H), 3.73 (s, 4H), 3.30 (d, J = 14.1 Hz, 4H), 3.04 (t, J = 6.9 Hz, 2H), 2.70 (t, J = 6.9 Hz, 2H), 2.58 (td, J = 6.8, 1.0 Hz, 4H), 2.51 (dd, J = 7.7, 6.4 Hz, 4H), 2.48 - 2.42 (m, 4H).13C NMR (100 MHz, cd3od) δ 174.80, 173.13, 139.44, 138.48, 128.26, 127.90, 38.62, 38.43, 34.90, 34.85, 30.13, 30.02, 28.89, 27.92. HR-ESI-TOF m / z calculated for C23H36N3O6S3+[M+H]+: 546.17608, found: 546.17839

[0207] Compound 3b (140 mg, 0.26 mmol) was dissolved in 1 mL of DMF containing 100 μL of DIPEA in a scintillation vial. Boc anhydride (70 mg, 0.32 mmol) dissolved in 0.2 mL of DMF was added to the mixture and the reaction was stirred overnight. DMF and DIPEA was removed under vacuum and the crude product was purified by prep-HPLC to afford 3c as a white solid. Yield 120 mg, 72%.1H NMR (400 MHz, cd3od) δ 7.20 (s, 3H), 3.72 (d, J = 2.1 Hz, 6H), 3.32 (d, J = 6.6 Hz, 4H), 3.18 (t, J = 7.0 Hz, 2H), 2.58 (td, J = 6.9, 1.0 Hz, 4H), 2.55 – 2.41 (m, 10H), 1.43 (s, 9H).13C NMR (100 MHz, cd3od) δ 174.77, 173.09, 156.91, 139.17, 139.08, 127.96, 78.75, 39.54, 38.64, 38.52, 34.92, 30.62, 30.18, 30.06, 28.92, 27.41. HR-ESI-TOF m / z calculated for C28H44N3O8S3+[M+H]+: 646.22851, found: 646.22843

[0208] Compound 3c (80 mg, 0.12 mmol) was dissolved in 1 mL of DMF, to which was added EDC (75 mg, 0.34 mmol) and NHS (57 mg, 0.5 mmol). The reaction was shaken overnight at room temperature The product was extracted with DCM (100 mL, twice) and 100 mL of water. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. DCM was removed by vacuum. The crude product was purified by silica gel chromatography. The desired product was eluted by 6% methanol in DCM to yield the KL3 linker as a white solid. Yield: 56 mg, 54%. HR-ESI-TOF m / z calculated for C36H50N5O12S3+[M+H]+: 840.26126, found: 840.26681.

[0209] Synthesis of the propargyl peptide. The propargyl containing peptides were synthesized by standard solid phase peptide synthesis on pre-loaded Fmoc-Lys(Boc)-Wang resin or Fmoc-Leu- Wang resin. Deprotection of Fmoc: The Fmoc removal was achieved by treatment with 20% piperidine in DMF for 5 min, twice. The resin was washed in DMF five times before the addition of activated amino acids. Coupling: A suspension of Fmoc protected amino acid (5 e.q., 0.5 M), HBTU (5 e.q., 0.5 M) and DIPEA (12.5 e.q., 1.25 M) in DMF was added to the vessel containing the resin. The mixture was shaken for 1 hour at room temperature For the Fmoc-Phe(CH2SO3H)-OH residue, the coupling time was extended to 3 h. The resin was washed in DMF five times after coupling. The final peptide was cleaved from the resin using a cleavage cocktail (TFA / TIPS / H2O, 95:2.5:2.5, 0.5 mL / 10 μmol) for 2 h. The solution was drained under pressurized nitrogen and the peptide was precipitated by cold ether (100x volume). The slurry was centrifuged at 1500 G, 4°C for 8 minutes to afford a white pellet. The pellet was dried under

[0071] 71 / 89#14461419v1 vacuum to remove the residual ether and redissolved in acetonitrile / water (1:2) for HPLC purification (Method C).

[0210] Synthesis of glycosulfopeptide (GSP) dimers. The dimers were synthesized as illustrated in Scheme S4. Briefly, two propargyl containing peptides were initially coupled by one of three linkers (KL1, KL2, KL3) through lysine residues positioned either at the N-terminus or the C- terminus of each peptide backbone. A sLexglycan was subsequently incorporated on each peptide backbone by copper-catalyzed azide-alkyne cycloaddition to afford the final dimeric glycosulfopeptide. A series of N- or the C-terminal dimeric glycosulfopeptides were designated as G4_KLn or CG4_KLn, respectively, where KLn indicates linker type KL1, KL2, or KL3.

[0211] Synthesis of the propargyl dimers. The propargyl peptide was dissolved in DMF (10% DIPEA) to a final concentration of 50 mM. A total of 0.3 e.q. of linker KL1, KL2 or KL3 was added to the solution. The reaction was allowed to proceed for 48 hours and quenched by the addition of acetic acid. The mixture was concentrated under vacuum to remove the solvents. Boc protection of the amino group was removed by treatment with neat TFA for 30 minutes and the TFA was removed by vacuum prior to purification. The propargyl dimer was isolated by reverse-phase preparative HPLC (prep-HPLC) with Method B. Yields: G4_KL1_propargyl 30%; G4_KL2_propargyl 35%; G4_KL3_propargyl 26%; CG4_KL1_propargyl 40%; CG4_KL2_propargyl 36%; CG4_KL3_propargyl 20%.

[0212] Synthesis of GSP dimers. The propargyl dimer (1 e.q.) was mixed with 1M copper sulfate (6 e.q.), 1M sodium ascorbate (8 e.q.) and THPTA (4 e.q.). A total of 2.5 e.q. of the sLexdissolved in DMF was immediately added to the mixture. The reaction was covered by aluminum foil and shaken for 16 hours at room temperature The desired product was isolated by prep-HPLC with Method B. Yields: G4_KL1: 53%, G4_KL2: 56%; G4_KL3: 50%; CG4_KL1: 55%; CG4_KL2: 55%; CG4_KL3: 47%. EQUIVALENTS ANDSCOPE

[0213] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0072] 72 / 89#14461419v1

[0214] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is / are referred to as comprising particular elements and / or features, certain embodiments of the present disclosure or aspects of the present disclosure consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0215] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0216] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

[0073] 73 / 89#14461419v1

Claims

CLAIMSWhat is claimed is:

1. A conjugate comprising Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein each of P1and P2are independently glycopeptides comprising the amino acid sequence: Y1X1Y2X2X3Y3X4X5X6Z1X7W1(SEQ ID NO: 1), wherein: W1is threonine or serine conjugated with a saccharide or polysaccharide; X1, X2, X3, X4, X5, X6, and X7are each independently any amino acid; Y1, Y2, and Y3are each independently tyrosine, phenylalanine, or phenylglycine, and wherein Y1, Y2, and Y3are each independently unsubstituted or substituted with -SO3H, - CH2SO3H, -CF2SO3H, -CO2H, -CONH2, -NHSO2CH3, -SO2NH2, or -CH2PO3H; optionally wherein at least one of Y1, Y2, and Y3is substituted with -CH2SO3H; Z1is proline or hydroxyproline; and L1is a linker.

2. The conjugate of claim 1, or a pharmaceutically acceptable salt thereof, wherein each of P1and P2are conjugated to L1via their N-termini.

3. The conjugate of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each of P1and P2are conjugated to L1via their C-termini.

4. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein P1is conjugated to L1via its N-terminus, and P2is conjugated to L1via its C- terminus.

5. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein P1is conjugated to L1via its C-terminus, and P2is conjugated to L1via its N- terminus.

6. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein P1and P2comprise the same amino acid sequence.

7. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt74 / 89#14461419v1thereof, wherein P1and P2comprise different amino acid sequences.

8. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein P1and P2independently comprise one of the following amino acid sequences: Y1EY2LDY3DFLZ1EW1(SEQ ID NO: 2), Y1EY2LDY3DFLZ1EW1EP (SEQ ID NO: 3), Y1EY2LDY3DFLZ1EW1EPL (SEQ ID NO: 4), EY1EY2LDY3DFLZ1EW1(SEQ ID NO: 5), EY1EY2LDY3DFLZ1EW1E (SEQ ID NO: 6), EY1EY2LDY3DFLZ1EW1EP (SEQ ID NO: 7), EY1EY2LDY3DFLZ1EW1EPL (SEQ ID NO: 8), KEY1EY2LDY3DFLZ1EW1(SEQ ID NO: 9), KEY1EY2LDY3DFLZ1EW1E (SEQ ID NO: 10), KEY1EY2LDY3DFLZ1EW1EP (SEQ ID NO: 11), KEY1EY2LDY3DFLZ1EW1EPL (SEQ ID NO: 12), EY1EY2LDY3DFLZ1EW1K (SEQ ID NO: 13), EY1EY2LDY3DFLZ1EW1EK (SEQ ID NO: 14), EY1EY2LDY3DFLZ1EW1EPK (SEQ ID NO: 15), or EY1EY2LDY3DFLZ1EW1EPLK (SEQ ID NO: 16).

9. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least two of Y1, Y2, and Y3are substituted with -CH2SO3H.

10. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each of Y1, Y2, and Y3are substituted with -CH2SO3H.

11. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Y1, Y2, and Y3are each phenylalanine.

12. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Y1, Y2, and Y3are each phenylalanine substituted with -CH2SO3H.

13. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein W1is threonine.75 / 89#14461419v114. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein W1is serine.

15. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each glycopeptide is independently conjugated to the saccharide or polysaccharide via click chemistry.

16. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each glycopeptide is independently conjugated to the saccharide or polysaccharide via a linker, L2.

17. The conjugate of claim 16, or a pharmaceutically acceptable salt thereof, wherein each L2independently comprises a triazole.

18. The conjugate of claim 17, or a pharmaceutically acceptable salt thereof, wherein each L2independently comprises a 1,2,3-triazole.

19. The conjugate of claim 18, or a salt thereof, wherein each L2is independently comprises one of the following structures:

20. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt76 / 89#14461419v1thereof, wherein the saccharide or polysaccharide comprises one or more sugars selected from the group consisting of: 2-(acetylamino)-2-deoxy-galactose, galactose, 2-(acetylamino)-2- deoxy-glucose, fucose, and 5-acetamido-3,5-dideoxy-glycero-galacto-2-nonulosonic acid.

21. The conjugate any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the polysaccharide is sialyl Lewis X or sialyl Lewis A.

22. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein the polysaccharide comprises a radical S1:and wherein L2is bonded to the anomeric oxygen of S1.

23. The conjugate of claim 22, or a pharmaceutically acceptable salt thereof, wherein the polysaccharide further comprises an α 1-3 bond between S1and a radical S2:

24. The conjugate of claim 23, or a pharmaceutically acceptable salt thereof, wherein the polysaccharide further comprises a β 1-4 bond between S1and a radical S3:

25. The conjugate of claim 24, or a pharmaceutically acceptable salt thereof, wherein the polysaccharide further comprises a β 1-3 bond between S3and a radical S4:77 / 89#14461419v126. The conjugate of claim 25, or a pharmaceutically acceptable salt thereof, wherein the polysaccharide is of the formula:.

27. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, X5, X6, and X7are each independently E, D, L, or F.

28. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X1, X2, X3, X4, X6, and X7are each independently E, D, or L.

29. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L1comprises optionally substituted arylene or optionally substituted heteroarylene.

30. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L1comprises optionally substituted phenylene.

31. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein L1comprises the formula:, wherein each R1is independently optionally substituted alkylene or optionally substituted heteroalkylene; and R2is hydrogen, optionally substituted alkyl, optionally substituted heteroalkyl, or a half-life extending moiety.

32. The conjugate of claim 31, or a pharmaceutically acceptable salt thereof, wherein L1comprises one of the following formulae:78 / 89#14461419v1, , or.

33. The conjugate of claim 31 or 32, or a pharmaceutically acceptable salt thereof, wherein L1comprises the formula:.

34. The conjugate of any one of claims 31-33, or a pharmaceutically acceptable salt thereof,wherein R3is polyethylene glycol (PEG) or methoxy-PEG (mPEG).

35. The conjugate of any one of claims 31-33, wherein R2comprises a fatty acid, a lipid, PEG, or methoxy-PEG.

36. The conjugate of any one of the preceding claims, wherein L1comprises one of the following formulae:79 / 89#14461419v137. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein one or both glycopeptides comprise an N-terminal acetyl moiety.

38. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, comprising the amino acid sequence: Ac-EY1EY2LDY3DFLZ1EW1EPLK-L1- KLPEW1EZ1LFDY3DLY2EY1E-Ac (SEQ ID NO: 17), wherein: W1is threonine conjugated to a polysaccharide; and Y1, Y2, and Y3are each independently phenylalanine substituted with -CH2SO3H.

39. The conjugate of claim 38, wherein the conjugate is selected from the group consisting of:,80 / 89#14461419v1O HO OO HOH NNO O N O HO HNOH HN NH O O O NO HNSN NO O N HO OH HO O NH OH Ac HN S NHAc NHOHO O SOHHCOH O O OH O OOONH S NHHOOOHO OH O O HN O H HN OH O HO OH O OH O O O O SOH O N NH O NH H HO OH H O SOH HO O OC HN O O H HOOOO O OH N N O HO AcHN H OH O HO OH HOS O OH HN NH HO HN O HN O O Ac HO ONO HOO HH ON OO HNN NH N N O NH NH N O H O O O H O N HO O O OH HOS OHN OHN N O H O NH O HOS N HN O HO O O HO , SOH OOHHO H O N OH O N H O Ac N O NH OH HN H O HO OH O O NH SOH COH O O H N HO NH HO OH S NH O OH S O H S HN O HO O HO O O O O O HN HO HO O HO S O NH AcHN O O OH HN O HN HN O O NH O O ONHN O N O O NH OH N NNONN O O N HN O OH HOOH N O O HN HO O O O NHAc O NHOO OH NH H N NH O O HOC OH O O HO ONHO OHOOOOH O HN OH HO OH H O O HO HN HO O Ac OH N HOSOO OHNH O NH OHON HO N N O N OH O O N HN OH H HO NH O HO NH HOS HOS O O HO , and pharmaceutically acceptable salts thereof.81 / 89#14461419v140. The conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, comprising the amino acid sequence: LPEW1EZ1LFDY3DLY2EY1EK-L1- KY1EY2LDY3DFLZ1EW1EPL (SEQ ID NO: 18), wherein: W1is threonine conjugated to a polysaccharide; and Y1, Y2, and Y3are each independently phenylalanine substituted with -CH2SO3H.

41. The conjugate of claim 40, wherein the conjugate is selected from the group consisting of:,82 / 89#14461419v1OH OH OH OH COH OH HOOOOH NNO O O HAcHOOHO AcHN O OH SOH OHNNN HO H O O NS SNH O HN O OOSOH SOH O O HO O O O O OOH O OH OO N NH H N NH H H H H H O N N N N N NN N OO N N N H HN O H H H H H N OH O NH O O O O O HN O HO O HO O HO O O HO O NH SOH O O HN HOS O NH OH O Ac HN HOS NH OH O H OH O O N HO O COH O HN O HOS OH O O HO N HO OH HO HO O O O O O OH HNAcHNOHO N O O NH O O N N HN ON O HN O OH OH O O OHO NO NH ,83 / 89#14461419v1OH OH OH OH COH OH HOOOOH N O O O AcHOOHO AcHN NNO N OH NHOH OHHO O O O O SOH SOH O O O HOH O OH OO N O H H O NH N N H O H H H N N N NN OO O N N N N NNH H H HN H H H O NH O O O O O N OH S O HO O HO O HO O O SOH S HN S OH OH OH OH OH COH HOOOOO H N O O O O HNAcHOOHAcHN NNO N OH O H OH OHO O NH O O SOH SOH O O O H O H O OOH O OH OO N NH H N H H H N N N N N N N N NN N OO HN H O H H O H H H O N OH O NH O O O HO O HO O HO O O SOH84 / 89#14461419v1H c O A NHO H H O O H O C O O O O N NNONH O H OON HO H H O O N O O N H Hc H OOO O A O O O H O H N O O H H O O H O O H O H O O C O H O O H H OH Nc A , O H85 / 89#14461419v1H c O A NHO H H O O H O C O O H H O O H O O O H O O H H c O O O H AH NOO H O O H ONNN H N O N O H OONHO HH NO O O ON HO O O N N H H OH NO O H O S NHO H OH NOH O O SN HO HNH O H O O SN HO H O HO NO O OH NO H N H O O ONO H O N N HN HHOHNH O S O O OHH NS O H N H O O O N S S O H OHN HH N ONH O S H N O S H O O O N HH O OH NN HO O N N Hc O A H O N O N NON N HNH O O O H O ON HO H H O O O O N H Hc H N O O A O O OH NO H O H N O H O H O O O H O H O H O O C I O H O O H H OH Nc A O H , and pharmaceutically acceptable salts thereof, wherein n is from 1-1000.

42. A pharmaceutical composition comprising the conjugate of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.86 / 89#14461419v143. The pharmaceutical composition of claim 42, further comprising an additional therapeutic agent.

44. The pharmaceutical composition of claim 42 or 43, which is formulated for intravenous, subcutaneous, or intramuscular administration.

45. The pharmaceutical composition of claim 42 or 43, in the form of a pill, tablet, capsule, or gel.

46. The pharmaceutical composition of any one of claims 42-44, comprising an aqueous saline buffer and wherein the pharmaceutically acceptable excipient is a saccharide or polysaccharide.

47. A method comprising administering to a subject a conjugate, or a pharmaceutically acceptable salt thereof, of any one of claims 1-41, or a pharmaceutical composition of any one of claims 42-46.

48. A method of inhibiting P-selectin binding to PSGL-1, comprising contacting the P- selectin with the conjugate, or pharmaceutically acceptable salt thereof, of any one of claims 1- 41.

49. A method of treating or preventing cardiovascular disease, atherosclerosis, atherosclerotic lesions, thrombus formation, thromboembolism, stroke, sickle cell disease, proliferative disease, metabolic syndrome, ischemia reperfusion injury, or myocardial infarction in a subject in need thereof, comprising administering to the subject an effective amount of the conjugate, or a pharmaceutically acceptable salt thereof, of any one of claims 1-41, or a pharmaceutical composition of any one of claims 42-46.

50. The method of claim 49, wherein the subject is at risk of, exhibiting symptoms of, or diagnosed with atherosclerosis, atherosclerotic lesions, thrombus formation, thromboembolism, stroke, or myocardial infarction.

51. The method of claim 49, wherein the subject has an increased risk of bleeding relative to that of a healthy adult.87 / 89#14461419v152. The method of claim 49, wherein the subject has a history of bleeding.

53. The method of claim 49, wherein the subject has a history of abnormal liver or kidney function or has increased fall risk.

54. The method of claim 49, wherein the thromboembolism is venous thromboembolism (VTE).

55. The method of claim 54, wherein the VTE is cancer-associated.

56. A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of the conjugate, or a pharmaceutically acceptable salt thereof, of any one of claims 1-41, or a pharmaceutical composition of any one of claims 42-46.

57. A method of thromboprophylaxis, comprising administering to a subject diagnosed with cancer an effective amount of the conjugate, or a pharmaceutically acceptable salt thereof, of any one of claims 1-41, or a pharmaceutical composition of any one of claims 42-46.

58. A method of treating or preventing allergy or lung disease in a subject in need thereof, comprising administering to the subject an effective amount of the conjugate, or a pharmaceutically acceptable salt thereof, of any one of claims 1-41, or a pharmaceutical composition of any one of claims 42-46.

59. The method of claim 58, wherein the subject is at risk of, exhibiting symptoms of, or diagnosed with asthma, bronchitis, emphysema, or chronic obstructive pulmonary disease (COPD).

60. A conjugate of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 42-46, for use in a method of any one of claims 47-59.

61. Use of a conjugate of any one of claims 1-41, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 42-46, in the preparation of a medicament.88 / 89#14461419v1

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